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Adding fuel to the fire: Immunogenic intensification a
a
Geraldine O’Sullivan Coyne & James L Gulley a
Genitourinary Malignancies Branch; Medical Oncology Service; National Cancer Institute; National Institutes of Health; Bethesda, MD USA Accepted author version posted online: 31 Oct 2014.Published online: 27 Jan 2015.
Click for updates To cite this article: Geraldine O’Sullivan Coyne & James L Gulley (2014) Adding fuel to the fire: Immunogenic intensification, Human Vaccines & Immunotherapeutics, 10:11, 3306-3312, DOI: 10.4161/21645515.2014.973318 To link to this article: http://dx.doi.org/10.4161/21645515.2014.973318
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REVIEW Human Vaccines & Immunotherapeutics 10:11, 3306--3312; November 2014
Adding fuel to the fire: Immunogenic intensification Geraldine O’Sullivan Coyne and James L Gulley* Genitourinary Malignancies Branch; Medical Oncology Service; National Cancer Institute; National Institutes of Health; Bethesda, MD USA
Keywords: activated T cell, cancer, checkpoint inhibitor, immunogenic intensification, PD-L1, vaccine
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Abbreviations: APC, antigen-presenting cells; TAP, transporter of antigen processing; CARs, chimeric antigen receptors; HER2, epidermal growth factor receptor 2; MHC I, major histocompatibility class I molecules; mCRPC, metastatic castration-resistant prostate cancer; mAB, monoclonal antibodies; MDSCs, myeloid-derived suppressor cells; PD-1, programmed death-1; PD-L1, programmed death-ligand-1; TAA, tumor-associated antigen; TILs, tumor infiltrating lymphocytes; Tregs, regulatory T cells.
The durable long term clinical benefits seen for certain patients treated with immunotherapy agents has suggested there is significant therapeutic potential to be derived from these agents, as shown by the increasing prominence of this treatment strategy in upcoming clinical trials. There has been a renewed interest and focus on the drivers of tumoral antigen recognition, and the pathways by which various cells of the immune system can stimulate, propagate and execute an effective anti-tumor response. Various challenges lie ahead in the further development of these treatments, including induction of an endogenous anti-tumor response, tumor microenvironment modulation, and T-cell response amplification. Novel treatment combinations may prove of significant added benefit by immunogenic intensification.
Introduction The immune system has classically denoted a collection of cells and interactive processes that protect the human organism from disease. In the past number of years, this definition has expanded through our increased knowledge of the role this system plays specifically in the development, control and dissemination of malignancy. The central tenet to the development of cancer immunotherapy has been the demonstration that the human immune system is able to produce specific lymphocytes following recognition of human tumor-associated antigens, though this concept has been known for more than 20 years.1,2 Boon and colleagues’ work with human melanoma cells demonstrated that despite effective antigen recognition in cancer patients, a nonprotective and weak anti-tumor response was elicited. Given the extensive literature demonstrating the lethality of a reactive T lymphocyte in the setting of allograph rejection and viral immunology, the impetus to harness an effective adaptive immune This article not subject to US copyright law. *Corresspondence to: James L Gulley; Email: [email protected] Submitted: 07/01/2014; Revised: 08/06/2014; Accepted: 08/20/2014 http://dx.doi.org/10.4161/21645515.2014.973318
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response to either eliminate or prevent recurrence of malignancy is of great clinical interest. The generic process of acquiring ‘immunity’ and the control of the same is well documented, and with the recent and growing impressive results of this approach in cancer therapeutics, it would appear that this will become part of mainstream cancer management. The genetic events that lead to the expression of tumor antigens on human cells have been previously reviewed.3 The association of these antigens with major histocompatibility class I molecules (MHC I) permits them to be recognized by specific CD8C T lymphocytes. This group of immune cells, with a common denominator of shared CD3 expression and that of an antigen-specific T-cell receptor (TCR), are known to regulate immune responses through highly specialized interactions between TCRs, antigens, co-stimulatory and co-inhibitory molecules to play a key role in the balance between autoimmunity and tolerance. They were originally described in the 1960s,4 and we know now how these cells mature in a stepwise fashion to become effector cells following the negative and positive selection processes in the thymus.5 A ‘danger signal’ or spark provides the necessary stimulus for antigen-presenting cells (APC) to process tumor-released antigens, making them MHC Class II-binding peptides via the endosome, or MHC class I-binding peptides by the proteasome depending on the specialized subcellular compartment that processes them.6,7 MHC Class I peptide epitopes are transferred to the endoplasmic reticulum by the transporter of antigen processing (TAP), where they associate with MHC Class I molecules and are translocated to the cell membrane surface for presentation to both CD4C and CD8C T cells.8 Conceptually, the MHC-peptide driven binding to the T cell receptor constitutes the ‘signal 1’ of T cell activation. The accessory signal, ‘signal 2’, is provided by the binding of a number of co-stimulatory molecules such as B7.1 or B7.2 to CD28. In general, it is the activated CD8C T cells that then migrate to a tumor, lysing malignant cells.9 APC-activated CD4C T cells can also initiate and amplify the CD8C T-cell response directly by providing co-stimulatory cytokines, or upregulating costimulatory molecules. Alternatively, transformed tumor antigens may present tumor antigens directly to CD8C and/or CD4C T cells, resulting also in tumor specific immunity (Fig. 1).3,6
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of the work on how T lymphocytes recognize antigens, as well as what exactly constitutes a tumor antigen and the sequential steps leading to presentation of these on MHC molecules has been done on mouse tumors. However, there has also been a great deal of work done on the identifying human tumor antigens of ‘high specificity’: where viral antigens, antigens resulting from mutation or re-arrangement of a gene-coding sequence, tissue lineage specific antigens or antigens overexpressed on tumor versus normal tissue, have been identified as the type of spark able to potentially elicit a tumor-specific immune response.3 This issue remains crucial for cancer immunotherapeutics as it will determine either a tumor-specific response or crossreactivity of activated T-cells which can undoubtedly lead to immune toxicities. The extent of the T-lymphocyte amplification response to an antigen is Figure 1. The Cancer-Immunity Cycle. (This figure has been reproduced with permission) balanced by co-stimulatory and inhibitory signals, the ‘immune check-points’; Tumors are now known to be associated with immune- and though normally they are pivotal for maintenance of selftolerance and immune-evasion, and this has led to the develop- tolerance, they have been increasingly recognized as a mechanism ment of various immune-based treatment strategies with the aim of tumoral immune evasion.18 One of these co-expressed moleto reactivate the adaptive and innate immune system against cules identified on T-lymphocytes is PD-1, and various trials expressed tumor antigens that have been recognized as ‘self.’10 have confirmed clinical activity for therapeutic monoclonal antiImmunotherapies which continue to be studied include adoptive bodies blocking the activity of this target.13,19 Programmed cellular therapy (e.g., T-cells expressing a chimeric antigen recep- death-ligand-1 (PD-L1 or B7.H1 or CD274) is a transmembrane tor [CAR]),11 monoclonal antibodies (mAB) against immune surface protein which interacts with PD-1; and shown to be checkpoint inhibitors (e.g.,, ipilimumab, mAB against cytotoxic expressed, oppositely, on APCs and on a variety of tumor T lymphocyte antigen-4 [CTLA-4]; and nivolumab, mAB cells.20,21 The PD-1:PDL-1 binding interaction conveys a negaagainst programmed death-1 [PD-1]12,13 and therapeutic vac- tive regulatory signaling cascade, thereby reducing T-cell prolifercines (such as sipuleucel-T and PSA-TRICOM).14,15 Approved ation and ultimately inducing immune tolerance.10 There are immunotherapies to date include Bacillus Calmette-Guerin treat- data to suggest that the presence of PD-L1 staining on cancer ments and sipuleucel-T for genitourinary malignancies, with ipi- cells is a marker of poor prognosis.21 PD-L1 upregulation on limumab approved for melanoma and a signaling cytokine tumor cells is known to be induced by interferon-g, normally (interleukin-2) for melanoma and clear cell renal carcinoma. produced by activated T-cells, and sustained PD-L1 expression is Intriguingly, the repeated finding of long-term clinical benefit associated with a T-cell exhaustion phenotype.18 Preclinical and (the ‘tail on the curve’) obtained by albeit a small group of preliminary clinical data have shown blockade of the PD1:PD-L1 patients in the immunotherapy clinical trials is compelling evi- bond can induce potent anti-tumor effects, and clinical responses dence to consider that there is a true therapeutic potential to this have been observed in various solid malignancies with either a sinapproach. However, because we now know that there are multi- gle-agent monoclonal blocking antibody (mAB)13,22 or in combiple mechanisms by which tumor cells can evade immune elimina- natorial treatment strategies.19 It is postulated that by blocking tion,16,17 it is possible that we can optimize the efficacy of PD-L1, T-cells will not become ‘de-activated’ in the tumor microenvironment in response to tumoral antigens and will facilitate immunotherapeutic agents through combination strategies. tumor cell lysis.18 This predominant effect, to unleash the activity of T-cells within the tumor microenvironment, is also hypotheChallenges to Current Immunotherapy Modalities: sized to generate a more focused immune response by leading to Potential Target Areas for Combination Strategies less likelihood of immune related adverse events than that seen with the more generalized immune activation caused by ipilimuThe main goal of cancer immunotherapy is to develop a mab.12 Though the principal effectors of the anti-tumor immune robust and efficacious anti-tumor immune response. A great deal response are cytotoxic T-lymphocytes (CTL),23,24 it is as
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yet unclear how different doses of anti-PD-L1 therapy will affect a given immune subset. It is also unclear if the biologically optimal dosing of these mAB corresponds to the maximally tolerated dose, as recent studies suggest impressive, and apparently non-inferior, clinical outcomes in dose levels below the maximally tolerated dose.25,26 It is, however, important to note that these data to date are from non-randomized trials. Another challenging area coming to the fore is the tumor microenvironment, which is now recognized to be involved in the homeostasis of the immune response.27,28 The multitude of cells that constitute the surroundings of transformed cells not only constitute a physical barrier to but also contribute to a tumor’s biology.29,30 The microenvironment has been shown to contain tumor infiltrating lymphocytes (TILs). These include regulatory cells such as CD4CCD25CFOXP3C regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), Thelper 2 (Th2) CD4CT cells, M2 macrophages and N2 neutrophils which are tasked with maintaining an immunologically ‘privileged’ or isolating sheath.29 Other immune cells, such as CD8CCTLs, T-helper 1 (Th1) and T-helper 17 (Th17) CD4CT cells, M1 macrophages, N1 neutrophils, natural killer cells and dendritic cells have been typically involved in antitumor responses, and progressively have been shown to modulate the local microenvironment for local angiogenic, metabolic and immune needs.9,27 The recognition of the impact of the tumor microenvironment infiltrate has led to the development of the ‘immune score’ as a histopathological measurement that has potential as a prognostic tool in human cancers, and is currently being validated in multiple centers around the world.6,31 The recognition of tumor infiltrating lymphocytes in malignant samples has retrospectively been shown to be predictive and prognostic of better treatment outcomes.31
Immunogenic Intensification The durable clinical responses that have been seen with immunotherapeutic cancer treatment strategies have driven the search for other immune modulators and have also given rise to the idea of combining immune therapy approaches, coined as ‘immunogenic intensification.’25 There are data to suggest that PD-L1 or PD-1 blockade alone is not sufficient for a clinical response9,28,32,33 though conversely some PD-L1 negative tumors can still respond to checkpoint inhibitor therapy.34 Given this, it would appear that an underlying immune response is required before it can be ‘unleashed’ following treatment with immune monotherapies. Activated tumor specific T-cells stimulate IFN production within the tumor environment, which in turns upregulates PD-L1 expression and can lead to ineffective T-cells. This would certainly support the premise of a better response and therefore clinical outcome when PD1/PD-L1 blockade is done in PD-L1 expressing tumors, which may be a marker of an ongoing anti-tumor immune response. Clinically, approaches that are actively being pursued are the combination of different immune checkpoint inhibitors and the combination of vaccines with immune checkpoint inhibitors, a
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‘double target’ strategy with the intent of obtaining synergistic activity and therefore clinical response (Table 1). Immunogenic intensification: Clinical data Combining immunotherapies in the clinical setting remains a concept being explored in clinical trials at this time. However, there are some early results to date that would suggest it is possible to combine immune agents with manageable side effects, while inducing effective anti-tumor activity. The immune combinations explored and presented to date include 2 checkpoint inhibitor combinations, vaccine-monoclonal antibody against the same TAA (tumor associated antigen) and vaccine-immune checkpoint inhibitor combinations. Wolchock et al demonstrated approximately one-half of the patients with melanoma receiving the highest dose of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) had an objective response, all of which appeared to be rapid, profound and durable (>80% reduction by RECIST) in this phase I trial. However, this was at the cost of an apparent increase in autoimmune toxicity, with one-half of the patients having grade 3 or greater adverse events.19 A recent update on the safety, clinical activity and survival of patients with this combination regimen was presented at the American Society of Clinical Oncology Annual Meeting in June 2014.35 This included data for both the original 53 patients, as well as preliminary results for a new 41 patient cohort. All of these 94 patients had stage III or IV malignant melanoma, and 55% of patients had not received prior systemic treatment. The induction schedule was the same for both cohorts of patients: nivolumab and ipilimumab every 3 weeks for 4 doses. The original 53 patients then received nivolumab every 3 weeks for 4 doses, followed by nivolumab and ipilimumab every 12 weeks for 8 doses. The 1 year overall survival (OS) rate was 85%, with the 2 year OS rate increasing to 79%. The confirmed CR rate for the initial cohort of patients also increased from 10% to 17%, though the authors speculated that it might be greater as 22 out of the original 53 patients had > 80% reduction in overall tumor measurements (41.5%). 18 of these patients with objective responses were ongoing, with a median time of response duration that was not yet reached. Clinical responses were recorded in patients regardless of their tumor PD-L1 or BRAF mutation status and across all dose levels. The subsequent 41 patients received nivolumab at 3 mg/kg every 2 weeks for up to 2 years. The reported objective response rate for these patients was 43%, which was similar to the original 53 patients. Grade 3/4 side effects did occur in 58 of the 94 patients (62%). The authors reported that these had all been manageable with the pre-established treatment algorithms for ipilimumab. A single toxic death was reported in the 41 patient cohort due to colitis but no new safety concerns arose. Though this trial design does not answer what are the benefits of sequential vs. combination treatment with these agents with regards to toxicity and survival, it does suggest that perhaps ipilimumab drives an immune response, some of which is directed at the tumor, and nivolumab ‘unlocks’ this response at the tumor site. Another interesting strategy reported to date has been the use of both a vaccine and a monoclonal antibody targeting an
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Table 1. Selected ongoing clinical trials using combination immune agents. Tumor Type Renal Cell Hodgkin’s lymphoma Pancreas Non-small cell Lung
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Non-small cell Lung Colon (MSIC) Glioblastoma Solid tumors Solid tumors Solid tumors x Solid tumors Solid tumors* Melanoma Melanoma Melanoma X Melanoma x Melanoma x Melanoma Melanoma x Melanoma
Experimental Combination nivolumabC/ipilimumab (or sunitinib, pazopanib) nivolumabCipilimumab FOLFIRINOX followed by ipilimumabCvaccine NivolumabC(platinum doublet chemo) or erlotinib or ipilimumab or bevacizumab vs monothrapyɸ MEDI4736/tremelimumab nivolumab vs ipilimumabCnivolumab Ipilimumab or ipilimumab C nivolumab vs bevacizumab lirilumabCnivolumaba Anti-LAG-3C/¡nivolumabb MEDI4736/tremelimumab rIL-21/nivolumab nivolumab vs nivolumabCipilimumab NY-ESO-1 vaccineCipilimumab1 NY-ESO-1 vaccineCipilimumab BCG followed by ipilimumab IpilimumabCnivolumab nivolumabCipilimumab vs ipilimumab TriMix-DCCipilimumab ipilimumab and nivolumab nivolumab C/¡ ipilimumab
Immune Target
Randomized
Phase
NCT number
PD-1/CTLA4 PD-1CCTLA4 CTLA4CGVAXp PD-1/CTLA4
No No Yes Yes
Phase I Phase I Phase II Phase I
NCT01472081 NCT01592370 NCT01896869 NCT01454102
Anti-PD-L1/CTLA4 PD-1/CTLA4 CTLA4/PD-1
No No Yes
Phase 1b Phase II Phase IIb
NCT02000947 NCT02060188 NCT02017717
KIR/PD-1 LAG-3/PD-1 Anti-PD-L1/CTLA4 Anti-PD-1 PD-1/PD-L1 NY-ESO-1/PD-L1 NY-ESO/CTLA4 CTLA4 CTLA4/PD-1 PD-1/CTLA4 caTLR4, CD70 & CD40L/CTLA4 CTLA4/PD-1 PD-1/CTLA4
No No No No Yes No No No No Yes No Yes (sequential) Yes
Phase I Phase I Phase I Phase I Phase I/II Phase I Phase I Phase I Phase Ib Phase II Phase II Phase II Phase III
NCT01714739 NCT01968109 NCT01975831 NCT01629758 NCT01928394 NCT01176474 NCT01810016 NCT01838200 NCT01024231 NCT01927419 NCT01302496 NCT01783938 NCT01844505
*5 types: triple negative breast cancer, pancreatic adenocarcinoma, gastric cancer, bladder cancer and small cell lung cancer. ɸ cisplatin/gemcitiabine or cisplatin/pemetrexed or carboplatin/paclitaxel. Bevacizumab as maintenance therapy. 1 Peptides: NY-ESO-1, BMS-936558, gp100:280-288(288V), or montanide. a Lirilumab (IPH2102/BMS-986015) is a fully human monoclonal antibody blocking interaction between Killer-cell immunoglobulin-like receptors (KIR) on NK cells and their ligands. b lymphocyte-activation gene 3. TriMix-DC: mRNA encoding CD40 ligand, constitutively active toll-like receptor 4, and CD70. X active trial but not recruiting. p GM-CSF-Transduced Pancreatic Tumor Cell Vaccine (GVAX).
identical TAA, in this case HER2 (Epidermal Growth Factor Receptor 2). In a phase I/II clinical trial, 22 patients with metastatic HER2 positive breast cancer were enrolled providing they had either a complete response or stable disease while on trastuzumab therapy and adequate left ventricular ejection fraction. Patients received up to 6 vaccinations with a HER2 T-helper peptide-based vaccine. Antigen specific T-cell immunity was assessed by interferon gamma enzyme-linked immunosorbent spot assay before, at midpoint, and at 1, 3, 6 and 12 months post vaccination. The vaccine was well tolerated, and only 15% of treated patients were found to have a reduction in their ejection fraction below the normal range. Tumor-specific responses were assessed by determining immunity to both HER2 intracellular and extracellular native sequence peptides (HLA-A2 binding motifs: p369.9, p688.9, and p972.9. Interestingly, 7 (37%) of 19 patients had pre-existing immunity to these HLA-A2 peptides, suggesting many patients had pre-existing immunity specific for HER2 while treated with trastuzumab alone. However, 14 patients (74%) significantly augmented the class I HER2/neu peptide-specific immune response following vaccination showing that immunity could be significantly boosted and maintained with vaccination. Intramolecular epitope spreading was also demonstrated by evidence of immunity to p98.15 and p776.15 (native epitopes of HER2/neu not included in the vaccine
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formulation). Nine (47%) of 19 patients had pre-existing immunity to these peptides. Fourteen patients (74%) significantly augmented the immune response, 5 patients (26%) did not augment, and none significantly decreased immunity to these peptides with immunization. The median follow-up among survivors was 36 months (range, 21 to 49 months), with a median progression free survival (PFS) of 17.7 months. The KaplanMeier estimate of PFS was 33% at 3 years. The median OS has not been reached; the Kaplan-Meier estimate of OS is 86% at 4 years.36 Combination studies have also explored the possibility of ‘directing’ the immune response by using a targeted vaccine, and then ‘unlocking’ the response with immune checkpoint inhibition. PSA-TRICOM (PROSTVACÒ ) is a vaccination strategy consisting of a single dose of recombinant vaccinia virus followed by recombinant fowlpox virus boosts.37,38 Both of these agents act as vectors, or carriers, and are structurally modified to express PSA and a triad of co-stimulatory molecules (B7.1, ICAM-1 and LFA-3) termed TRICOM. The rationale behind this design is to enhance antigen-presentation to the immune system, as PSA is one of the many TAAs expressed by prostate cancer cells. A phase I trial of 30 patients treated with ipilimumab in combination with PROSTVAC assessed the safety and tolerability of escalating doses of ipilimumab in combination with a fixed dose of
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PROSTVAC in patients with both docetaxel-refractory and chemotherapy-na€ıve metastatic castration-resistant prostate cancer patients (mCRPC).39 Of the 24 patients that were chemotherapy-na€ıve, 14 (58%) had a PSA decline from baseline, with 6 of these being greater than 50%. Only one of the docetaxelrefractory patients had a PSA decline from baseline. Median OS of patients on the combination arm was 34.4 months, (with a median Halabi predicted survival of 17.2 months). The rates of immune-related adverse events in the combination arm were similar to those for patients treated with ipilimumab alone (including endocrinopathies and colitis) with no dose limiting toxicities reported. A published analysis of immune correlates from this trial population demonstrated trends toward associations for longer OS with specific immune subsets pre-treatment.40 This combination strategy of vaccine and checkpoint inhibitor has been assessed in another phase I dose escalation trial. This evaluated chemotherapy-na€ıve mCRPC patients treated with GVAX (a non-replicating adenovirus-based tumor cell vaccine which produces granulocyte macrophage colony-stimulating factor) together with concurrent ipilimumab for 24 weeks. OS was reported to be 29.2 months, with PSA declines >50% for 25% of the patients.41 Interestingly, T-cell evaluation showed that a prolonged OS was associated with patients with high pre-treatment levels of CD4CCTLA4C, CD4CPD-L1C cells. Presence of CD4CCTLA4C unsupervised T-cell clustering was found to be predictive of survival after GVAX/ipilimumab therapy,42 again demonstrating the significance of immune biomarkers for patient selection in immunotherapy trials. These trials also set the rational basis for further combination studies between vaccines and anti-PD-1 or anti-PD-L1 inhibition, which could lead to exciting results.
Immunogenic Cell Death versus Immunogenic Modulation The goal of obtaining an endogenous anti-tumor response has prompted a careful exploration of cell death as the pivotal start point. The proposal of immunogenic cell death, that is, a tumor cell death that can act as an auto-‘vaccine’ by being taken up by APCs and stimulating a specific T-cell response, has been previously explored,43 and follows a similar pathway to the well documented recognition of viral pathological antigens. However, the recognition that conventional cytotoxic therapies may modulate tumor phenotype in a way that can upregulate the immune system has been termed immunogenic modulation and may indeed be more clinically relevant for patients in the context of tumor cells that survive direct cell lysis, as well as enhance broader antigen spreading and recognition kill.44,45 Clinical studies of immunotherapy combined with radiation therapy, chemotherapy or other modalities such as androgendeprivation therapy have been shown to mediate immunogenic cell death, in which the dying tumor cells are taken up by the immune system and processed, resulting in an antitumor immune response.46 Another rationale to this type of combination is the idea of ‘debulking’ a tumor with either effective local
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or systemic therapy. Indeed, there is a growing amount of clinical evidence that would suggest the efficacy of conventional cytotoxic chemotherapy lies in its ability to stimulate the innate and adaptive immune system. However, the pleiotropic effects of chemotherapy, the lack of generalized effect between agents, and the apparent impact of both the dose and timing of these means more studies are needed to better integrate chemoimmunotherapy into clinical practice.47
Conclusions The complex nature of malignant disease cannot be underestimated: it is not limited only to a definition as a genetic disease with multiple genetic and epigenetic abnormalities; there are multiple broader aspects such as tumor – host interactions, including those with the immune system, now being recognized as playing an important role. By approaching cancer treatment considering a single genetic aspect, the quest for targeted or personalized therapy has defined a major part of cancer research in the past decades. However, even in the setting of good responses to cytotoxic or targeted therapy, the disease generally inevitably progresses. Emerging immunotherapy data suggest that patients can experience both durable and long-term progression-free or disease-free survival. The immune system has the capacity to develop or expand exquisitely specific responses, and with the creation of effective memory cells can continue effective ‘seek and kill’ strategies against malignant cells beyond the withdrawal of therapy. Furthermore, the capability of the immune system to recognize novel targets generated by tumors, such as new mutations, highlights the adaptability of this approach.48 Beyond the issue of development of these innovative immunotherapeutic treatment strategies, various hurdles remain. Separately from the potential clinical benefits, there are presently few markers that can predict which patients may actually be the ones to benefit or demonstrate which immune pathway dominates a certain tumor, and dynamic analysis of both serum, circulating tumor markers and tissue are ongoing in multiple studies. The unique set of side effects associated with these agents will require careful monitoring and prompt treatment algorithms to minimize toxicity. And, whether as monotherapy or combination, we will need to define appropriate end-points of clinical benefit as the traditional evaluation of response may be inadequate in the setting of immune cell infiltration of tumors.49 The stimulation of an endogenous anti-tumor response is the key step to unlocking an effective anti-tumor immune response; however this initial smoldering reaction appears to be amplified, magnified and sustained by setting the immune system free when adding a second immune strategy. We expect the ongoing efforts in combination immune-based clinical trials to further elucidate these issues.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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PMID:20100959; http://dx.doi.org/10.1200/ JCO.2009.25.0597 Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 2007; 25:267-96; PMID:17134371; http://dx.doi.org/10.1146/annurev. immunol.25.022106.141609 Wolf D, Heine A, Brossart P. Implementing combinatorial immunotherapeutic regimens against cancer: The concept of immunological conditioning. Oncoimmunology 2014; 3:e27588; PMID:24800168; http://dx. doi.org/10.4161/onci.27588 Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12:25264; PMID:22437870; http://dx.doi.org/10.1038/ nrc3239 Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369:122-33; PMID:23724867; http://dx.doi.org/10.1056/ NEJMoa1302369 Flies DB, Chen L. The new B7s: playing a pivotal role in tumor immunity. J Immunother 2007; 30:251-60; PMID:17414316; http://dx.doi.org/10.1097/CJI.0b 013e31802e085a Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, Sengupta S, Frank I, Parker AS, Zincke H, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res 2006; 66:3381-5; PMID:16585157; http://dx.doi.org/10.1158/00085472.CAN-05-4303 Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366:2455-65; PMID:22658128; http://dx.doi. org/10.1056/NEJMoa1200694 Chouaib S. Integrating the quality of the cytotoxic response and tumor susceptibility into the design of protective vaccines in tumor immunotherapy. J Clin Invest 2003; 111:595-7; PMID:12618511; http://dx. doi.org/10.1172/JCI18044 Vacchelli E, Vitale I, Tartour E, Eggermont A, SautesFridman C, Galon J, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Anticancer radioimmunotherapy. Oncoimmunology 2013; 2:e25595; PMID:24319634; http://dx.doi.org/10.4161/onci.25595 O’Sullivan Coyne G, Madan RA, Gulley JL. Nivolumab: promising survival signal coupled with limited toxicity raises expectations. J Clin Oncol 2014; 32:986-8. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 2014; 32:1020-30; PMID:24590637; http://dx.doi. org/10.1200/JCO.2013.53.0105 Senovilla L, Vacchelli E, Galon J, Adjemian S, Eggermont A, Fridman WH, Sautes-Fridman C, Ma Y, Tartour E, Zitvogel L, et al. Trial watch: Prognostic and predictive value of the immune infiltrate in cancer. Oncoimmunology 2012; 1:1323-43; PMID:23243596; http://dx.doi. org/10.4161/onci.22009 Gajewski TF, Fuertes M, Spaapen R, Zheng Y, Kline J. Molecular profiling to identify relevant immune resistance mechanisms in the tumor microenvironment. Curr Opin Immunol 2011; 23:286-92; PMID:21185705; http://dx. doi.org/10.1016/j.coi.2010.11.013 Emens LA, Silverstein SC, Khleif S, Marincola FM, Galon J. Toward integrative cancer immunotherapy: targeting the tumor microenvironment. J Transl Med 2012; 10:70; PMID:22490302; http://dx.doi.org/ 10.1186/1479-5876-10-70 Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer
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suppression and promotion. Science 2011; 331:156570; PMID:21436444; http://dx.doi.org/10.1126/ science.1203486 Galon J, Pages F, Marincola FM, Thurin M, Trinchieri G, Fox BA, Gajewski TF, Ascierto PA. The immune score as a new possible approach for the classification of cancer. J Transl Med 2012; 10:1; PMID:22214470; http://dx.doi.org/10.1186/1479-5876-10-1 Gajewski TF. Cancer immunotherapy. Mol Oncol 2012; 6:242-50; PMID:22248437; http://dx.doi.org/ 10.1016/j.molonc.2012.01.002 Gajewski TF, Woo SR, Zha Y, Spaapen R, Zheng Y, Corrales L, Spranger S. Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol 2013; 25:268-76; PMID:23579075; http://dx.doi.org/ 10.1016/j.coi.2013.02.009 Powderly JD, Koeppen H, Hodi FS, Sosman JA, Gettinger SN, Desai R, Tabernero J, Soria J, Hamid O, Fine G, et al. Biomarkers and associations with the clinical activity of PD-L1 blockade in a MPDL3280A study. J Clin Oncol 2013; 31(suppl):abstr 3001. Sznol M, Kluger H, Callahan MK, Postow MA, Gordon RA, Segal NH, Rizvi NA, Lesokhin AM, Atkins MB, Kirkwood J, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). J Clin Oncol 2014; 32(5s):abstr LBA9003. Disis ML, Wallace DR, Gooley TA, Dang Y, Slota M, Lu H, Coveler AL, Childs JS, Higgins DM, Fintak PA, et al. Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer. J Clin Oncol 2009; 27:4685-92; PMID:19720923; http://dx.doi.org/10.1200/JCO.2008.20.6789 Arlen PM, Skarupa L, Pazdur M, Seetharam M, Tsang KY, Grosenbach DW, Feldman J, Poole DJ, Litzinger M, Steinberg SM, et al. Clinical safety of a viral vector based prostate cancer vaccine strategy. J Urol 2007; 178:1515-20; PMID:17707059; http://dx.doi.org/ 10.1016/j.juro.2007.05.117 Madan RA, Arlen PM, Mohebtash M, Hodge JW, Gulley JL. Prostvac-VF: a vector-based vaccine targeting PSA in prostate cancer. Expert Opin Investig Drugs 2009; 18:1001-11; PMID:19548854; http://dx.doi. org/10.1517/13543780902997928 Madan RA, Mohebtash M, Arlen PM, Vergati M, Rauckhorst M, Steinberg SM, Tsang KY, Poole DJ, Parnes HL, Wright JJ, et al. Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol 2012; 13:501-8; PMID:22326924; http://dx.doi.org/10.1016/S14702045(12)70006-2 Jochems C, Tucker JA, Tsang KY, Madan RA, Dahut WL, Liewehr DJ, Steinberg SM, Gulley JL, Schlom J. A combination trial of vaccine plus ipilimumab in metastatic castration-resistant prostate cancer patients: immune correlates. Cancer Immunol Immunother 2014; 63:407-18; PMID:24514956; http://dx.doi.org/ 10.1007/s00262-014-1524-0 van den Eertwegh AJ, Versluis J, van den Berg HP, Santegoets SJ, van Moorselaar RJ, van der Sluis TM, Gall HE, Harding TC, Jooss K, Lowy I, et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol 2012; 13:509-17; PMID:22326922; http://dx.doi.org/10.1016/S14702045(12)70007-4 Santegoets SJ, Stam AG, Lougheed SM, Gall H, Scholten PE, Reijm M, Jooss K, Sacks N, Hege K, Lowy I, et al. T cell profiling reveals high CD4CCTLA-4 C T cell frequency as dominant predictor for survival after prostate GVAX/ipilimumab treatment. Cancer
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45. Singh B, Gulley JL. Therapeutic vaccines as a promising treatment modality against prostate cancer: rationale and recent advances. Ther Adv Vaccines 20 June 2014 [Epub ahead of print]. 46. Zitvogel L, Apetoh L, Ghiringhelli F, Andre F, Tesniere A, Kroemer G. The anticancer immune response: indispensable for therapeutic success? J Clin Invest 2008; 118:1991-2001; PMID:18523649; http://dx. doi.org/10.1172/JCI35180 47. Emens LA. Chemoimmunotherapy. Cancer J 2010; 16:295-303; PMID:20693839; http://dx.doi.org/ 10.1097/PPO.0b013e3181eb5066
48. Gulley JL. Therapeutic vaccines: the ultimate personalized therapy? Hum Vaccin Immunother 2013; 9:21921; PMID:22995839; http://dx.doi.org/10.4161/ hv.22106 49. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, Maio M, Binder M, Bohnsack O, Nichol G, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15:7412-20; PMID:19934295; http://dx.doi.org/10.1158/10780432.CCR-09-1624
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Immunol Immunother 2013; 62:245-56; PMID:22878899; http://dx.doi.org/10.1007/s00262012-1330-5 43. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol 2013; 31:51-72; PMID:23157435; http://dx.doi.org/ 10.1146/annurev-immunol-032712-100008 44. Hodge JW, Garnett CT, Farsaci B, Palena C, Tsang KY, Ferrone S, Gameiro SR. Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death. Int J Cancer 2013; 133:624-36; PMID:23364915; http://dx.doi.org/10.1002/ijc.28070
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Human Vaccines & Immunotherapeutics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/khvi20
Adding fuel to the fire: Immunogenic intensification a
a
Geraldine O’Sullivan Coyne & James L Gulley a
Genitourinary Malignancies Branch; Medical Oncology Service; National Cancer Institute; National Institutes of Health; Bethesda, MD USA Accepted author version posted online: 31 Oct 2014.Published online: 27 Jan 2015.
Click for updates To cite this article: Geraldine O’Sullivan Coyne & James L Gulley (2014) Adding fuel to the fire: Immunogenic intensification, Human Vaccines & Immunotherapeutics, 10:11, 3306-3312, DOI: 10.4161/21645515.2014.973318 To link to this article: http://dx.doi.org/10.4161/21645515.2014.973318
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REVIEW Human Vaccines & Immunotherapeutics 10:11, 3306--3312; November 2014
Adding fuel to the fire: Immunogenic intensification Geraldine O’Sullivan Coyne and James L Gulley* Genitourinary Malignancies Branch; Medical Oncology Service; National Cancer Institute; National Institutes of Health; Bethesda, MD USA
Keywords: activated T cell, cancer, checkpoint inhibitor, immunogenic intensification, PD-L1, vaccine
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Abbreviations: APC, antigen-presenting cells; TAP, transporter of antigen processing; CARs, chimeric antigen receptors; HER2, epidermal growth factor receptor 2; MHC I, major histocompatibility class I molecules; mCRPC, metastatic castration-resistant prostate cancer; mAB, monoclonal antibodies; MDSCs, myeloid-derived suppressor cells; PD-1, programmed death-1; PD-L1, programmed death-ligand-1; TAA, tumor-associated antigen; TILs, tumor infiltrating lymphocytes; Tregs, regulatory T cells.
The durable long term clinical benefits seen for certain patients treated with immunotherapy agents has suggested there is significant therapeutic potential to be derived from these agents, as shown by the increasing prominence of this treatment strategy in upcoming clinical trials. There has been a renewed interest and focus on the drivers of tumoral antigen recognition, and the pathways by which various cells of the immune system can stimulate, propagate and execute an effective anti-tumor response. Various challenges lie ahead in the further development of these treatments, including induction of an endogenous anti-tumor response, tumor microenvironment modulation, and T-cell response amplification. Novel treatment combinations may prove of significant added benefit by immunogenic intensification.
Introduction The immune system has classically denoted a collection of cells and interactive processes that protect the human organism from disease. In the past number of years, this definition has expanded through our increased knowledge of the role this system plays specifically in the development, control and dissemination of malignancy. The central tenet to the development of cancer immunotherapy has been the demonstration that the human immune system is able to produce specific lymphocytes following recognition of human tumor-associated antigens, though this concept has been known for more than 20 years.1,2 Boon and colleagues’ work with human melanoma cells demonstrated that despite effective antigen recognition in cancer patients, a nonprotective and weak anti-tumor response was elicited. Given the extensive literature demonstrating the lethality of a reactive T lymphocyte in the setting of allograph rejection and viral immunology, the impetus to harness an effective adaptive immune This article not subject to US copyright law. *Corresspondence to: James L Gulley; Email: [email protected] Submitted: 07/01/2014; Revised: 08/06/2014; Accepted: 08/20/2014 http://dx.doi.org/10.4161/21645515.2014.973318
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response to either eliminate or prevent recurrence of malignancy is of great clinical interest. The generic process of acquiring ‘immunity’ and the control of the same is well documented, and with the recent and growing impressive results of this approach in cancer therapeutics, it would appear that this will become part of mainstream cancer management. The genetic events that lead to the expression of tumor antigens on human cells have been previously reviewed.3 The association of these antigens with major histocompatibility class I molecules (MHC I) permits them to be recognized by specific CD8C T lymphocytes. This group of immune cells, with a common denominator of shared CD3 expression and that of an antigen-specific T-cell receptor (TCR), are known to regulate immune responses through highly specialized interactions between TCRs, antigens, co-stimulatory and co-inhibitory molecules to play a key role in the balance between autoimmunity and tolerance. They were originally described in the 1960s,4 and we know now how these cells mature in a stepwise fashion to become effector cells following the negative and positive selection processes in the thymus.5 A ‘danger signal’ or spark provides the necessary stimulus for antigen-presenting cells (APC) to process tumor-released antigens, making them MHC Class II-binding peptides via the endosome, or MHC class I-binding peptides by the proteasome depending on the specialized subcellular compartment that processes them.6,7 MHC Class I peptide epitopes are transferred to the endoplasmic reticulum by the transporter of antigen processing (TAP), where they associate with MHC Class I molecules and are translocated to the cell membrane surface for presentation to both CD4C and CD8C T cells.8 Conceptually, the MHC-peptide driven binding to the T cell receptor constitutes the ‘signal 1’ of T cell activation. The accessory signal, ‘signal 2’, is provided by the binding of a number of co-stimulatory molecules such as B7.1 or B7.2 to CD28. In general, it is the activated CD8C T cells that then migrate to a tumor, lysing malignant cells.9 APC-activated CD4C T cells can also initiate and amplify the CD8C T-cell response directly by providing co-stimulatory cytokines, or upregulating costimulatory molecules. Alternatively, transformed tumor antigens may present tumor antigens directly to CD8C and/or CD4C T cells, resulting also in tumor specific immunity (Fig. 1).3,6
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of the work on how T lymphocytes recognize antigens, as well as what exactly constitutes a tumor antigen and the sequential steps leading to presentation of these on MHC molecules has been done on mouse tumors. However, there has also been a great deal of work done on the identifying human tumor antigens of ‘high specificity’: where viral antigens, antigens resulting from mutation or re-arrangement of a gene-coding sequence, tissue lineage specific antigens or antigens overexpressed on tumor versus normal tissue, have been identified as the type of spark able to potentially elicit a tumor-specific immune response.3 This issue remains crucial for cancer immunotherapeutics as it will determine either a tumor-specific response or crossreactivity of activated T-cells which can undoubtedly lead to immune toxicities. The extent of the T-lymphocyte amplification response to an antigen is Figure 1. The Cancer-Immunity Cycle. (This figure has been reproduced with permission) balanced by co-stimulatory and inhibitory signals, the ‘immune check-points’; Tumors are now known to be associated with immune- and though normally they are pivotal for maintenance of selftolerance and immune-evasion, and this has led to the develop- tolerance, they have been increasingly recognized as a mechanism ment of various immune-based treatment strategies with the aim of tumoral immune evasion.18 One of these co-expressed moleto reactivate the adaptive and innate immune system against cules identified on T-lymphocytes is PD-1, and various trials expressed tumor antigens that have been recognized as ‘self.’10 have confirmed clinical activity for therapeutic monoclonal antiImmunotherapies which continue to be studied include adoptive bodies blocking the activity of this target.13,19 Programmed cellular therapy (e.g., T-cells expressing a chimeric antigen recep- death-ligand-1 (PD-L1 or B7.H1 or CD274) is a transmembrane tor [CAR]),11 monoclonal antibodies (mAB) against immune surface protein which interacts with PD-1; and shown to be checkpoint inhibitors (e.g.,, ipilimumab, mAB against cytotoxic expressed, oppositely, on APCs and on a variety of tumor T lymphocyte antigen-4 [CTLA-4]; and nivolumab, mAB cells.20,21 The PD-1:PDL-1 binding interaction conveys a negaagainst programmed death-1 [PD-1]12,13 and therapeutic vac- tive regulatory signaling cascade, thereby reducing T-cell prolifercines (such as sipuleucel-T and PSA-TRICOM).14,15 Approved ation and ultimately inducing immune tolerance.10 There are immunotherapies to date include Bacillus Calmette-Guerin treat- data to suggest that the presence of PD-L1 staining on cancer ments and sipuleucel-T for genitourinary malignancies, with ipi- cells is a marker of poor prognosis.21 PD-L1 upregulation on limumab approved for melanoma and a signaling cytokine tumor cells is known to be induced by interferon-g, normally (interleukin-2) for melanoma and clear cell renal carcinoma. produced by activated T-cells, and sustained PD-L1 expression is Intriguingly, the repeated finding of long-term clinical benefit associated with a T-cell exhaustion phenotype.18 Preclinical and (the ‘tail on the curve’) obtained by albeit a small group of preliminary clinical data have shown blockade of the PD1:PD-L1 patients in the immunotherapy clinical trials is compelling evi- bond can induce potent anti-tumor effects, and clinical responses dence to consider that there is a true therapeutic potential to this have been observed in various solid malignancies with either a sinapproach. However, because we now know that there are multi- gle-agent monoclonal blocking antibody (mAB)13,22 or in combiple mechanisms by which tumor cells can evade immune elimina- natorial treatment strategies.19 It is postulated that by blocking tion,16,17 it is possible that we can optimize the efficacy of PD-L1, T-cells will not become ‘de-activated’ in the tumor microenvironment in response to tumoral antigens and will facilitate immunotherapeutic agents through combination strategies. tumor cell lysis.18 This predominant effect, to unleash the activity of T-cells within the tumor microenvironment, is also hypotheChallenges to Current Immunotherapy Modalities: sized to generate a more focused immune response by leading to Potential Target Areas for Combination Strategies less likelihood of immune related adverse events than that seen with the more generalized immune activation caused by ipilimuThe main goal of cancer immunotherapy is to develop a mab.12 Though the principal effectors of the anti-tumor immune robust and efficacious anti-tumor immune response. A great deal response are cytotoxic T-lymphocytes (CTL),23,24 it is as
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yet unclear how different doses of anti-PD-L1 therapy will affect a given immune subset. It is also unclear if the biologically optimal dosing of these mAB corresponds to the maximally tolerated dose, as recent studies suggest impressive, and apparently non-inferior, clinical outcomes in dose levels below the maximally tolerated dose.25,26 It is, however, important to note that these data to date are from non-randomized trials. Another challenging area coming to the fore is the tumor microenvironment, which is now recognized to be involved in the homeostasis of the immune response.27,28 The multitude of cells that constitute the surroundings of transformed cells not only constitute a physical barrier to but also contribute to a tumor’s biology.29,30 The microenvironment has been shown to contain tumor infiltrating lymphocytes (TILs). These include regulatory cells such as CD4CCD25CFOXP3C regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), Thelper 2 (Th2) CD4CT cells, M2 macrophages and N2 neutrophils which are tasked with maintaining an immunologically ‘privileged’ or isolating sheath.29 Other immune cells, such as CD8CCTLs, T-helper 1 (Th1) and T-helper 17 (Th17) CD4CT cells, M1 macrophages, N1 neutrophils, natural killer cells and dendritic cells have been typically involved in antitumor responses, and progressively have been shown to modulate the local microenvironment for local angiogenic, metabolic and immune needs.9,27 The recognition of the impact of the tumor microenvironment infiltrate has led to the development of the ‘immune score’ as a histopathological measurement that has potential as a prognostic tool in human cancers, and is currently being validated in multiple centers around the world.6,31 The recognition of tumor infiltrating lymphocytes in malignant samples has retrospectively been shown to be predictive and prognostic of better treatment outcomes.31
Immunogenic Intensification The durable clinical responses that have been seen with immunotherapeutic cancer treatment strategies have driven the search for other immune modulators and have also given rise to the idea of combining immune therapy approaches, coined as ‘immunogenic intensification.’25 There are data to suggest that PD-L1 or PD-1 blockade alone is not sufficient for a clinical response9,28,32,33 though conversely some PD-L1 negative tumors can still respond to checkpoint inhibitor therapy.34 Given this, it would appear that an underlying immune response is required before it can be ‘unleashed’ following treatment with immune monotherapies. Activated tumor specific T-cells stimulate IFN production within the tumor environment, which in turns upregulates PD-L1 expression and can lead to ineffective T-cells. This would certainly support the premise of a better response and therefore clinical outcome when PD1/PD-L1 blockade is done in PD-L1 expressing tumors, which may be a marker of an ongoing anti-tumor immune response. Clinically, approaches that are actively being pursued are the combination of different immune checkpoint inhibitors and the combination of vaccines with immune checkpoint inhibitors, a
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‘double target’ strategy with the intent of obtaining synergistic activity and therefore clinical response (Table 1). Immunogenic intensification: Clinical data Combining immunotherapies in the clinical setting remains a concept being explored in clinical trials at this time. However, there are some early results to date that would suggest it is possible to combine immune agents with manageable side effects, while inducing effective anti-tumor activity. The immune combinations explored and presented to date include 2 checkpoint inhibitor combinations, vaccine-monoclonal antibody against the same TAA (tumor associated antigen) and vaccine-immune checkpoint inhibitor combinations. Wolchock et al demonstrated approximately one-half of the patients with melanoma receiving the highest dose of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) had an objective response, all of which appeared to be rapid, profound and durable (>80% reduction by RECIST) in this phase I trial. However, this was at the cost of an apparent increase in autoimmune toxicity, with one-half of the patients having grade 3 or greater adverse events.19 A recent update on the safety, clinical activity and survival of patients with this combination regimen was presented at the American Society of Clinical Oncology Annual Meeting in June 2014.35 This included data for both the original 53 patients, as well as preliminary results for a new 41 patient cohort. All of these 94 patients had stage III or IV malignant melanoma, and 55% of patients had not received prior systemic treatment. The induction schedule was the same for both cohorts of patients: nivolumab and ipilimumab every 3 weeks for 4 doses. The original 53 patients then received nivolumab every 3 weeks for 4 doses, followed by nivolumab and ipilimumab every 12 weeks for 8 doses. The 1 year overall survival (OS) rate was 85%, with the 2 year OS rate increasing to 79%. The confirmed CR rate for the initial cohort of patients also increased from 10% to 17%, though the authors speculated that it might be greater as 22 out of the original 53 patients had > 80% reduction in overall tumor measurements (41.5%). 18 of these patients with objective responses were ongoing, with a median time of response duration that was not yet reached. Clinical responses were recorded in patients regardless of their tumor PD-L1 or BRAF mutation status and across all dose levels. The subsequent 41 patients received nivolumab at 3 mg/kg every 2 weeks for up to 2 years. The reported objective response rate for these patients was 43%, which was similar to the original 53 patients. Grade 3/4 side effects did occur in 58 of the 94 patients (62%). The authors reported that these had all been manageable with the pre-established treatment algorithms for ipilimumab. A single toxic death was reported in the 41 patient cohort due to colitis but no new safety concerns arose. Though this trial design does not answer what are the benefits of sequential vs. combination treatment with these agents with regards to toxicity and survival, it does suggest that perhaps ipilimumab drives an immune response, some of which is directed at the tumor, and nivolumab ‘unlocks’ this response at the tumor site. Another interesting strategy reported to date has been the use of both a vaccine and a monoclonal antibody targeting an
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Table 1. Selected ongoing clinical trials using combination immune agents. Tumor Type Renal Cell Hodgkin’s lymphoma Pancreas Non-small cell Lung
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Non-small cell Lung Colon (MSIC) Glioblastoma Solid tumors Solid tumors Solid tumors x Solid tumors Solid tumors* Melanoma Melanoma Melanoma X Melanoma x Melanoma x Melanoma Melanoma x Melanoma
Experimental Combination nivolumabC/ipilimumab (or sunitinib, pazopanib) nivolumabCipilimumab FOLFIRINOX followed by ipilimumabCvaccine NivolumabC(platinum doublet chemo) or erlotinib or ipilimumab or bevacizumab vs monothrapyɸ MEDI4736/tremelimumab nivolumab vs ipilimumabCnivolumab Ipilimumab or ipilimumab C nivolumab vs bevacizumab lirilumabCnivolumaba Anti-LAG-3C/¡nivolumabb MEDI4736/tremelimumab rIL-21/nivolumab nivolumab vs nivolumabCipilimumab NY-ESO-1 vaccineCipilimumab1 NY-ESO-1 vaccineCipilimumab BCG followed by ipilimumab IpilimumabCnivolumab nivolumabCipilimumab vs ipilimumab TriMix-DCCipilimumab ipilimumab and nivolumab nivolumab C/¡ ipilimumab
Immune Target
Randomized
Phase
NCT number
PD-1/CTLA4 PD-1CCTLA4 CTLA4CGVAXp PD-1/CTLA4
No No Yes Yes
Phase I Phase I Phase II Phase I
NCT01472081 NCT01592370 NCT01896869 NCT01454102
Anti-PD-L1/CTLA4 PD-1/CTLA4 CTLA4/PD-1
No No Yes
Phase 1b Phase II Phase IIb
NCT02000947 NCT02060188 NCT02017717
KIR/PD-1 LAG-3/PD-1 Anti-PD-L1/CTLA4 Anti-PD-1 PD-1/PD-L1 NY-ESO-1/PD-L1 NY-ESO/CTLA4 CTLA4 CTLA4/PD-1 PD-1/CTLA4 caTLR4, CD70 & CD40L/CTLA4 CTLA4/PD-1 PD-1/CTLA4
No No No No Yes No No No No Yes No Yes (sequential) Yes
Phase I Phase I Phase I Phase I Phase I/II Phase I Phase I Phase I Phase Ib Phase II Phase II Phase II Phase III
NCT01714739 NCT01968109 NCT01975831 NCT01629758 NCT01928394 NCT01176474 NCT01810016 NCT01838200 NCT01024231 NCT01927419 NCT01302496 NCT01783938 NCT01844505
*5 types: triple negative breast cancer, pancreatic adenocarcinoma, gastric cancer, bladder cancer and small cell lung cancer. ɸ cisplatin/gemcitiabine or cisplatin/pemetrexed or carboplatin/paclitaxel. Bevacizumab as maintenance therapy. 1 Peptides: NY-ESO-1, BMS-936558, gp100:280-288(288V), or montanide. a Lirilumab (IPH2102/BMS-986015) is a fully human monoclonal antibody blocking interaction between Killer-cell immunoglobulin-like receptors (KIR) on NK cells and their ligands. b lymphocyte-activation gene 3. TriMix-DC: mRNA encoding CD40 ligand, constitutively active toll-like receptor 4, and CD70. X active trial but not recruiting. p GM-CSF-Transduced Pancreatic Tumor Cell Vaccine (GVAX).
identical TAA, in this case HER2 (Epidermal Growth Factor Receptor 2). In a phase I/II clinical trial, 22 patients with metastatic HER2 positive breast cancer were enrolled providing they had either a complete response or stable disease while on trastuzumab therapy and adequate left ventricular ejection fraction. Patients received up to 6 vaccinations with a HER2 T-helper peptide-based vaccine. Antigen specific T-cell immunity was assessed by interferon gamma enzyme-linked immunosorbent spot assay before, at midpoint, and at 1, 3, 6 and 12 months post vaccination. The vaccine was well tolerated, and only 15% of treated patients were found to have a reduction in their ejection fraction below the normal range. Tumor-specific responses were assessed by determining immunity to both HER2 intracellular and extracellular native sequence peptides (HLA-A2 binding motifs: p369.9, p688.9, and p972.9. Interestingly, 7 (37%) of 19 patients had pre-existing immunity to these HLA-A2 peptides, suggesting many patients had pre-existing immunity specific for HER2 while treated with trastuzumab alone. However, 14 patients (74%) significantly augmented the class I HER2/neu peptide-specific immune response following vaccination showing that immunity could be significantly boosted and maintained with vaccination. Intramolecular epitope spreading was also demonstrated by evidence of immunity to p98.15 and p776.15 (native epitopes of HER2/neu not included in the vaccine
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formulation). Nine (47%) of 19 patients had pre-existing immunity to these peptides. Fourteen patients (74%) significantly augmented the immune response, 5 patients (26%) did not augment, and none significantly decreased immunity to these peptides with immunization. The median follow-up among survivors was 36 months (range, 21 to 49 months), with a median progression free survival (PFS) of 17.7 months. The KaplanMeier estimate of PFS was 33% at 3 years. The median OS has not been reached; the Kaplan-Meier estimate of OS is 86% at 4 years.36 Combination studies have also explored the possibility of ‘directing’ the immune response by using a targeted vaccine, and then ‘unlocking’ the response with immune checkpoint inhibition. PSA-TRICOM (PROSTVACÒ ) is a vaccination strategy consisting of a single dose of recombinant vaccinia virus followed by recombinant fowlpox virus boosts.37,38 Both of these agents act as vectors, or carriers, and are structurally modified to express PSA and a triad of co-stimulatory molecules (B7.1, ICAM-1 and LFA-3) termed TRICOM. The rationale behind this design is to enhance antigen-presentation to the immune system, as PSA is one of the many TAAs expressed by prostate cancer cells. A phase I trial of 30 patients treated with ipilimumab in combination with PROSTVAC assessed the safety and tolerability of escalating doses of ipilimumab in combination with a fixed dose of
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PROSTVAC in patients with both docetaxel-refractory and chemotherapy-na€ıve metastatic castration-resistant prostate cancer patients (mCRPC).39 Of the 24 patients that were chemotherapy-na€ıve, 14 (58%) had a PSA decline from baseline, with 6 of these being greater than 50%. Only one of the docetaxelrefractory patients had a PSA decline from baseline. Median OS of patients on the combination arm was 34.4 months, (with a median Halabi predicted survival of 17.2 months). The rates of immune-related adverse events in the combination arm were similar to those for patients treated with ipilimumab alone (including endocrinopathies and colitis) with no dose limiting toxicities reported. A published analysis of immune correlates from this trial population demonstrated trends toward associations for longer OS with specific immune subsets pre-treatment.40 This combination strategy of vaccine and checkpoint inhibitor has been assessed in another phase I dose escalation trial. This evaluated chemotherapy-na€ıve mCRPC patients treated with GVAX (a non-replicating adenovirus-based tumor cell vaccine which produces granulocyte macrophage colony-stimulating factor) together with concurrent ipilimumab for 24 weeks. OS was reported to be 29.2 months, with PSA declines >50% for 25% of the patients.41 Interestingly, T-cell evaluation showed that a prolonged OS was associated with patients with high pre-treatment levels of CD4CCTLA4C, CD4CPD-L1C cells. Presence of CD4CCTLA4C unsupervised T-cell clustering was found to be predictive of survival after GVAX/ipilimumab therapy,42 again demonstrating the significance of immune biomarkers for patient selection in immunotherapy trials. These trials also set the rational basis for further combination studies between vaccines and anti-PD-1 or anti-PD-L1 inhibition, which could lead to exciting results.
Immunogenic Cell Death versus Immunogenic Modulation The goal of obtaining an endogenous anti-tumor response has prompted a careful exploration of cell death as the pivotal start point. The proposal of immunogenic cell death, that is, a tumor cell death that can act as an auto-‘vaccine’ by being taken up by APCs and stimulating a specific T-cell response, has been previously explored,43 and follows a similar pathway to the well documented recognition of viral pathological antigens. However, the recognition that conventional cytotoxic therapies may modulate tumor phenotype in a way that can upregulate the immune system has been termed immunogenic modulation and may indeed be more clinically relevant for patients in the context of tumor cells that survive direct cell lysis, as well as enhance broader antigen spreading and recognition kill.44,45 Clinical studies of immunotherapy combined with radiation therapy, chemotherapy or other modalities such as androgendeprivation therapy have been shown to mediate immunogenic cell death, in which the dying tumor cells are taken up by the immune system and processed, resulting in an antitumor immune response.46 Another rationale to this type of combination is the idea of ‘debulking’ a tumor with either effective local
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or systemic therapy. Indeed, there is a growing amount of clinical evidence that would suggest the efficacy of conventional cytotoxic chemotherapy lies in its ability to stimulate the innate and adaptive immune system. However, the pleiotropic effects of chemotherapy, the lack of generalized effect between agents, and the apparent impact of both the dose and timing of these means more studies are needed to better integrate chemoimmunotherapy into clinical practice.47
Conclusions The complex nature of malignant disease cannot be underestimated: it is not limited only to a definition as a genetic disease with multiple genetic and epigenetic abnormalities; there are multiple broader aspects such as tumor – host interactions, including those with the immune system, now being recognized as playing an important role. By approaching cancer treatment considering a single genetic aspect, the quest for targeted or personalized therapy has defined a major part of cancer research in the past decades. However, even in the setting of good responses to cytotoxic or targeted therapy, the disease generally inevitably progresses. Emerging immunotherapy data suggest that patients can experience both durable and long-term progression-free or disease-free survival. The immune system has the capacity to develop or expand exquisitely specific responses, and with the creation of effective memory cells can continue effective ‘seek and kill’ strategies against malignant cells beyond the withdrawal of therapy. Furthermore, the capability of the immune system to recognize novel targets generated by tumors, such as new mutations, highlights the adaptability of this approach.48 Beyond the issue of development of these innovative immunotherapeutic treatment strategies, various hurdles remain. Separately from the potential clinical benefits, there are presently few markers that can predict which patients may actually be the ones to benefit or demonstrate which immune pathway dominates a certain tumor, and dynamic analysis of both serum, circulating tumor markers and tissue are ongoing in multiple studies. The unique set of side effects associated with these agents will require careful monitoring and prompt treatment algorithms to minimize toxicity. And, whether as monotherapy or combination, we will need to define appropriate end-points of clinical benefit as the traditional evaluation of response may be inadequate in the setting of immune cell infiltration of tumors.49 The stimulation of an endogenous anti-tumor response is the key step to unlocking an effective anti-tumor immune response; however this initial smoldering reaction appears to be amplified, magnified and sustained by setting the immune system free when adding a second immune strategy. We expect the ongoing efforts in combination immune-based clinical trials to further elucidate these issues.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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