BBAMCR-17194; No. of pages: 7; 4C: 3 Biochimica et Biophysica Acta xxx (2014) xxx–xxx

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Can calcium signaling be harnessed for cancer immunotherapy?☆,☆☆ Ronald Rooke ⁎ Transgene SA, 400Bd Gonthier d'Andernach, Parc d'Innovation, CS80166, 67405 Illkirch Graffenstaden, France

a r t i c l e

i n f o

Article history: Received 26 December 2013 Accepted 29 January 2014 Available online xxxx Keywords: Immunology Oncology Active immunotherapy Passive immunotherapy Calcium signaling

a b s t r a c t Experimental evidence shows the importance of the immune system in controlling tumor appearance and growth. Immunotherapy is defined as the treatment of a disease by inducing, enhancing or suppressing an immune response. In the context of cancer treatment, it involves breaking tolerance to a cancer-specific selfantigen and/or enhancing the existing anti-tumor immune response, be it specific or not. Part of the complexity in developing such treatment is that cancers are selected to escape adaptive or innate immune responses. These escape mechanisms are numerous and they may cumulate in one cancer. Moreover, different cancers of a same type may present different combinations of escape mechanisms. The limited success of immunotherapeutics in the clinic as stand-alone products may in part be explained by the fact that most of them only activate one facet of the immune response. It is important to identify novel methods to broaden the efficacy of immunotherapeutics. Calcium signaling is central to numerous cellular processes, leading to immune responses, cancer growth and apoptosis induced by cancer treatments. Calcium signaling in cancer therapy and control will be integrated to current cancer immunotherapy approaches. This article is part of a Special Issue entitled: Calcium Signaling in Health and Disease. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Cancer is one of the most devastating pathologies in terms of epidemiology and outcome. In the world, 14 million new cases occurred in 2012 with 8 million deaths. Interestingly, there is less variation in mortality than in incidence between more developed and less developed countries (http://globocan.iarc.fr). This demonstrates that prevention in the western world plays a significant role in identifying cancer patients but having a larger choice of treatment modalities has a limited impact on this disease. The social costs of cancer are enormous (200 billion USD in the US in 2008) and the World Health Organization projects an increase in cancer related deaths from 7.6 million in 2008 to 13.1 million in 2030 worldwide (http://www.who.int/topics/cancer). Although treatment options are numerous, they all share limited success and toxicity. An underexploited tool in this arsenal is the use of the immune system to fight the patient's own cancer. This paradigm is known as immunotherapy and an important body of preclinical data shows that all arms of the human immune system are involved [1]. Ample approaches have been or are being evaluated in clinical settings and in many cases, they have generated disappointing results [2]. Many reasons can explain these results and the accumulating information from immunotherapy-based clinical trials demonstrates that this approach will best perform when used in combination with additional ☆ This article is part of a Special Issue entitled: Calcium Signaling in Health and Disease. ☆☆ The author declares no conflict of interest. ⁎ Tel.: +33 6 85 96 85 28. E-mail address: [email protected].

anti-cancer treatments [3]. These may either be standard of care or novel anti-cancer treatments. From this standpoint, calcium signaling is clearly over-looked in cancer therapy in general and particularly in the context of an immune intervention targeting cancers. Calcium is central in many biological processes including the elaboration and the control of an immune response [4]. Modification of calcium signaling to enhance tumor-targeting immunity could be done at the level of the innate arm of the immune stimulation. Besides being possibly sufficient to control cancer growth, it is required for proper antigen presentation to the immune system and development of the specific response [5]. Calcium signaling also plays an important role in the elaboration of an adaptive, antigen-specific, immune response which is thought crucial in the control of cancer. The latter intervention could act by enhancing or by preventing the resorption of the effector response directed against the cancer or the environment upon which it strives. It may also act by relieving the cancer-induced immunosuppression. Enhancing the efficacy of immunotherapy may give this technology the potential of controlling and/or eliminating tumors on a stand-alone basis but also to have additive effects on cancer growth when used with standard of care therapies [6]. This concept comes from their nonoverlapping modes of action. The former generally involve inhibiting cell division yielding an intrinsic cell death signal while immunotherapy acts by extrinsic cytotoxic mechanisms driven by immune mediators. More recently, synergy between the two treatment modalities has been proposed [7]. Indeed, in addition to their specific, non-redundant effects, cell death pathways induced by some chemotherapeutic drugs, radiotherapy or photodynamic therapy are immunostimulatory and could thereby enhance the efficacy of an immune intervention. Finally,

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the generation of an anamnestic anti-tumor response may impact on tumor reoccurrence and metastasis. Calcium is involved in all these steps and controlling its metabolism punctually and/or locally could significantly help in the anti-tumor control [8]. 2. History In its broadest definition, immunotherapy is the treatment of a disease by inducing, enhancing or dampening an immune response. Immunotherapy may therefore be applied to any condition in which an immune component is involved and ranges from inflammation and autoimmunity, in which the goal is to diminish an exacerbated immune response, to chronic infections and cancer where the immune response must be boosted. The concept that the immune response has a role in controlling cancer has existed for many years but has only been convincingly demonstrated recently [1]. This was done by first inducing tumors with a carcinogen in either immunodeficient or immunocompetent mice. Each tumor was then split in half with one half being grafted in an immunodeficient animal and the other in an immunocompetent animal (Fig. 1). It was observed that cancers taken from immunodeficient animals grew when transplanted in similarly immunodeficient animals but that they were rejected when transplanted in immunocompetent animals. Conversely, cancers arising in immunocompetent animals had the capacity to grow in either type of grafted mouse. These results show that spontaneously arising tumors are immunogenic, that the immune system is capable of eliminating them and more importantly, that the immune system exerts a selective pressure on the cancer and selects out cells that have the capacity to evade this immune response. The role of immune-surveillance in controlling cancer initiation and progression has also been indisputably demonstrated by the increase frequency of various types of cancers in immunodeficient mouse strains (reviewed in [1]). In a more clinically relevant setting, the demonstration that the intra-tumoral cytotoxic T cell infiltrate (CD8+) is correlated with a favorable outcome of the patient treatment and that it can be used as a predictive marker shows that the immune response existing in a patient undeniably plays a role in controlling the cancer's evolution even in the context of standard of care therapies [9]. The concept that the immune system may be used in the treatment of cancer originates from serendipitous observations made in the late 18th century which associated cancer regression and infections. The first immunotherapeutic intervention per se was developed by William Coley, in 1893 in which a mixture of killed Streptococcus pyogenes and Neisseria marcescens was used to treat several types of cancers [10].

This product was commercialized for 70 years before being classified as a “new drug” by the FDA in 1963. This limited its use to clinical trials that yielded unclear results and production was stopped. Since this period, important technological advances, a better understanding of immune mechanisms and their interaction with cancer has led to the preclinical and clinical evaluations of numerous compounds and approaches to harness the patient's immune response to their cancer. While this field is rapidly evolving, to date, only a handful of products are commercialized and are the backbone of only 3% of cancer therapies. This is expected to go up to 60% in the next 10 years and represents a potential market of 35 billion USD (http://www.reuters.com/article/2013/05/22/ us-cancer-immunotherapy-idUSBRE94L0CF20130522). The oldest approved cancer immunotherapeutic product still in use is the tuberculosis vaccine Bacille Calmet–Guérin (BCG) which was approved in 1976 to treat early, non-invasive bladder cancer [11]. It is believed to act by binding to urothelial carcinoma cells, causing a modification in the cytokine and chemokine milieu which will attract phagocytes. These latter cells produce Th1-type cytokines which will orient the immune response toward a more cytotoxic response [12].

3. Definitions Immunotherapeutic interventions applied to cancer are generally classified as either active or passive (Fig. 2). The former may be non-specific and involves a general stimulation of the immune system achieved with molecules such as cytokines. In this instance, tumor control may be exerted by innate immune mechanisms and/or the pre-existing antigen-specific immune response, independent of the knowledge of the antigen. At the other end of the spectrum of active immunotherapy, an immune response directed to an antigen expressed specifically or mainly on cancer cells may be achieved by therapeutic vaccination. The common denominator of this type of treatment is the exposure of the host's immune system to a given cancer antigen in a context such that it will stimulate a specific response [13]. An alternative active approach is termed adoptive T cell transfer (ATCT) (reviewed in [14]). It consists in amplifying ex vivo patient's tumor infiltrating lymphocytes (TILs), or cells from the blood, in conditions that will enrich for cells that express a T cell receptor (TCR) recognizing a tumor antigen presented in the context of syngeneic major histocompatibility complex (MHC). This procedure has been further modified by engineering ex vivo amplified effector T cells with retroviruses or lentiviruses to make them express a receptor specific for an antigen [15].

Fig. 1. Cancer immunoediting experiment. See text for details. Graphs below describe tumor volume (Y axis) vs time (X axis).

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Fig. 2. Cancer immunotherapy interventions. See text for details.

Passive immunotherapy involves the use of antibodies that recognize proteins necessary for the development of cancer and that do not stimulate the host's immune response [16]. Besides blocking the interaction between the ligand and its receptor, some of these antibodies mediate their beneficial effect via immune mechanisms such as Antibody Dependent Cell Cytotoxicity (ADCC) or Complement Dependent Cytotoxicity (CDC). A very promising approach is the association between passive and active immunotherapy which creates a new class of agents termed “checkpoint blockers” [17]. It involves the use of antibodies, as in passive immunotherapy, that act on molecules expressed by cells of the immune system that play a role in the maintenance of the immune response, similar to active immunotherapy. Each of these approaches will be detailed in following sections. 4. Cytokines The advent of recombinant DNA technology had a profound impact on immunotherapy. The possibility to clone genes encoding cytokines, have them expressed in bacteria or eukaryotic cells to produce large quantities of protein that can be purified in well characterized lots gave the possibility to test a number of cytokines in the clinic. This lead to the approval of interferon alpha (IFNα) to treat hairy cell leukemia in 1986 going along the then popular idea that most cancers were virally induced [18]. Interleukin-2 (IL-2) was tested during the same period in the clinic and was approved in 1996 to treat metastatic melanoma based on a clinical trial in which 6% of patients had a complete response to treatment and 10% a partial response [19]. It also has been developed and is used to treat metastatic renal cell carcinoma [20]. Since then, little improvement has been made for these pathologies and IL-2 remains one of the only treatment options for late stage disease. Other cytokines are currently being evaluated in clinical trials in oncology, such as IL-7, IL-12, IL-15, IL-21 and GM-CSF and clinical results are pending [21]. 5. Cancer vaccines Although a few proteins were known to be overexpressed by cancer cells in the 70s (carcinoembryonic antigen, α-phetoprotein, mucin-1, prostate specific antigen, etc.), they were essentially used as biomarkers [22]. It is in 1991 that it was first demonstrated that cancer cells could express antigens with an otherwise restricted expression pattern and

that they could be recognized by cytotoxic T lymphocytes [23]. This led to the identification of numerous other tumor antigens and opened the door to cancer vaccines (reviewed in [24]). In essence, it involves generating or recalling an immune response to a target protein known to be represented mainly on the cancer cells with limited distribution in normal tissues. Classical as well as innovative vaccine technologies have been used to test this family of products, each having their strong points and weaknesses (Table 1). These range from HLA-restricted peptides combined to various immunological adjuvants to intramuscular injection of plasmid DNA accompanied with electroporation of the injected area. Although the pre-clinical data, generally obtained in mouse models, using these highly appealing approaches are convincing, the clinical data have been disappointing in terms of patient's benefit [25]. Indeed, the confounded data accumulating over the last 20 years on cancer vaccines, either used as stand-alone or in combination with standard therapies, yield a picture in which generally 20% of patients respond [26]. This has been partly explained by two important observations that have impacted on the landscape of cancer immunotherapy. The first of these observations comes from the immunomonitoring performed during clinical trials on vaccinated patients. The obvious goal of this work is to identify or correlate the effector immune mechanisms with the patient's response. In spite of a significant investment in terms of the assays used and their standardization, to date, no obvious correlation can be done between the immune response generated by the vaccination and the outcome of the disease. The absence of tumor control in face of a demonstrable immune response suggests that the tumor-induced immunosuppression overrides the immune response in a majority of cases [27]. It therefore appears crucial to relieve this immunosuppression to enhance the efficacy of cancer vaccines. The second point stemming from these observations is that in many instances, the design of the clinical trials are based on what has been done for small molecules in which case the effect on tumor cells is fast and the impact on the tumor mass is rapid. Many clinical trials evaluating cancer vaccines have failed to meet their primary endpoint because cancer evolution was measured over a time period too short for a full-blown immune response to set in and/ or to have a significant effect on the tumor mass. Moreover, long-term follow-up of vaccinated patients shows a dichotomy between survival and tumor volume [28,29]. This suggests the non-mutually exclusive possibilities that vaccination switches back the tumor evolution to the equilibrium phase of cancer immunoediting or that the local immune response precludes measuring changes in tumor volumes by current

Please cite this article as: R. Rooke, Can calcium signaling be harnessed for cancer immunotherapy?, Biochim. Biophys. Acta (2014), http:// dx.doi.org/10.1016/j.bbamcr.2014.01.034

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Table 1 General technologies developed for cancer vaccines. Dendritic cells may be autologous or heterologous. The cytokines used in their production impact on the response generated. DNA vaccines may be electroporated in humans after injection. Tumor cells may be autologous or heterologous and/or genetically manipulated to express cytokines. Vectors encompass bacteria, viruses, retroviruses, and yeasts. Others include RNA vaccination, peptide strings, and fusion protein. Source: Pharma etrack. Vaccine

Proportion in clinical trials

Pros

Cons

Dendritic cells

17%

–Difficult to produce

DNA

4%

Tumor cell Vector based Proteins

10% 5% 17%

Peptide

14%

–One approved product –Differentiation in absence of immunosuppression –Possibility to orient differentiation –Easy to produce –No size limit for expressed gene –Many antigens may be targeted at once –No adjuvant needed –No HLA restriction –Easy to produce –Easy to produce

Others

33%

methodologies. Data driven discussions with regulatory agencies and hindsight on clinical results have been central in changing the field's point of view. It is also becoming clear that not all patients may benefit from an immunotherapeutic intervention and that early clinical trials including a dedicated biomarker identification approach and patients stratification allow the identification of a responding patient subpopulation [30]. This is exemplified by the START Phase III clinical trial ran by Merck-Serono in which the product L-BLP25 (tecemotide) has failed to meet its primary endpoint of improving overall survival in late stage Non-small Cell Lung Cancer (NSCLC) [31]. Nonetheless, Merck is pursuing the development of this product in the START2 phase III trial based on the data from an exploratory analysis of a predefined subgroup of patients in the START trial who received tecemotide after concurrent chemoradiotherapy (CRT: combination of chemotherapy and radiotherapy given at the same time). These patients achieved a median OS of 30.8 months versus 20.6 months for patients treated with placebo (n = 806; HR: 0.78; 95% CI: 0.64–0.95; p = 0.016). This illustrates that it is important that future clinical trials are designed and adapted to properly evaluate the ideal conditions of use of immunotherapeutics and identify the responding patient population. Calcium signaling has never been exploited in this context and may offer an edge in this endeavor. 6. Adoptive cell transfer The demonstration that T cells are present in cancer patients and that they react to cancer antigens has also justified an original approach in which in vitro-amplified tumor antigen-specific T cells taken from resected tumor or patient's blood are re-infused in the same patient. Coined adoptive T cell transfer, and in opposition to classical vaccination, it consists in the amplification of a functional T cell population outside of the immunosuppressed environment of the patient [32]. As for most personalized medicine approaches, the development and eventual commercialization of this type of product represent a challenge worth being taken up in face of the promising clinical benefit which shows objective cancer regression in more than 50% of melanoma patients and efficacy in other solid and hematological cancers [33,34]. Moreover, the capacity to genetically modify these cells with a receptor specific to a tumor antigen prior to reinfusion enhances the efficacy of this approach and broadens the number of indications in which it can be used. T cells can be modified to express either the T cell receptor that is the most represented in the TILs, the one isolated from the T cell population responding to a specific antigen in vitro or with chimeric antigen receptors (CARs). This latter technology involves transducing in vitroamplified T cells with a lentivirus expressing the fused variable portions of a monoclonal antibody heavy and light chains (scFv) linked to a transmembrane domain itself fused to the intracellular signaling domain of the CD3ζ protein [35]. It alleviates the T cells from MHC

–Poor immune response in human –Difficult to produce –May be impacted by standard of care –Requires adjuvant –HLA restriction –Requires adjuvant

restriction and the associated mechanisms needed for proper T cell stimulation such as antigen processing, presentation and costimulation that may be modified in the tumor context. Rather, it targets the transduced population to a molecule overexpressed on the cancer. The first generation of CAR constructs was first shown to work in vitro in the late 80s by Z Eshnar [36]. These constructs were then tested in a number of indications in the clinic and saw their efficacy limited to some partial responses, stable diseases and few remissions only in glioblastoma and B cell lymphoma. Since that time, second and third generation CARs have been developed by adding, respectively, one or multiple additional signaling domains from various co-stimulatory molecules [37,38]. These are currently being tested in the clinic and preclinic respectively and are showing promising results with some complete remissions. However, severe toxic effects were seen with second and third generation CARs and caution must be taken when administering these therapeutic entities [39]. Target-specific, off-cancer effect may in part be the culprit for this toxicity but cytokines released by this relatively long-lived cell population may also account for these deleterious effects. Possible solutions to this problem is to increase the specificity of the chimeric receptors to limit their effect to cancer cells and/or the inclusion of a suicide gene in the modified T cells so that a prodrug may be administered and this population eliminated upon adverse events. Finally, given the personalized nature of this method, the future of this field lies in the development of production methods which would make it available to more patients and ideally, commercializable at a competitive cost [33]. One successful cancer immunotherapy product which partly meets these criteria and based on adoptive transfer of autologous cells is Provenge also referred to as Sipuleucel-T [40]. It has been approved for commercialization by the Food and Drug Administration (FDA) in 2010 and by the European Medical Agency (EMA) in 2013 for the treatment of minimally symptomatic, castration-resistant androgen independent metastatic prostate cancer. It consists of getting the patient's dendritic cells (DC) by leukapheresis, stimulating them in vitro by exposing them to a recombinant human protein made of a fusion of the prostatic acid phosphatase protein, serving as the prostate cancerspecific antigen cancer, and the cytokine granulocyte-macrophage colony stimulating factor (GM-CSF) needed to stimulate the DC. The cells are then injected in the patients. The clinical benefit is statistically significant in this pathology and pushes the median survival by 4.1 months although the precise mode of action remains to be determined. It is interesting to note that the first Biological License Application (BLA) submitted in 2007 was turned down by the FDA as the organization asked for more data but also expressed concerns about the complexity and standardization of the manufacturing process. A number of companies are currently developing similar products with various proprietary DC maturation protocols that should impact on the nature of the immune response generated in the patients after reinfusion [41].

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7. Passive immunotherapy and monoclonal antibodies The development and the capacity to produce monoclonal antibodies was another crucial technological step that played a very important role in passive immunotherapy [42]. The hybridoma technology was first described in 1973 by Schwaber and Cohen and involves fusing a mouse myeloma having lost its capacity to produce antibodies with normal B cells from immunized mice and selecting a clone producing an antibody specific for a target antigen [43]. It became rapidly obvious that injecting mouse antibodies in humans induced an anti-mouse antibody response and formation of immune complexes causing rapid elimination of the injected protein and poor effector functions [44]. To circumvent this, DNA sequences coding for the variable parts of the mouse antibody were grafted to the sequences coding for the human constant region generating chimeric antibodies. This was further improved by Greg Winter in 1988 when he modified the regions flanking the variable sequences with conserved human sequences generating what are now called humanized antibodies [45]. The first commercialized antibody in oncology, used in the treatment of non-Hodgkin lymphoma in 1997, is the anti-CD20 antibody Rituximab. Over the following 16 years, 13 other antibodies interacting with a total of 8 molecular targets have gained FDA approval in oncology (Table 2) [16]. Bevacizumab binds VEGF-A, blocks its interaction with its receptor and inhibits neo-vascularization. It is the only antibody which binds a soluble target [46]. All the other antibodies used in oncology exert their anti-tumor function by various, non-mutually exclusive mechanisms. By binding to CD20 or CD52 in the treatment of non-Hodgkin lymphoma or chronic lymphocytic leukemia, some antibodies directly induce apoptosis [47]. This may be a direct effect on the targeted receptor or by its cross-linking due to the capacity of the antibody to bind, via its constant region, to the Fcγ receptor, present on NK cells and cells from the granulocytic/myeloid lineage. Most of the antibodies in oncology are of the IgG1 isotype and can therefore bridge the target cells with the Fcγ receptor and mediate ADCC, and/or antibody-dependent phagocytosis [48,49]. By engineering the Fc portion or modifying the glycosylation pattern, the interaction with the FcR can be decreased or enhanced impacting on its lytic activity [49]. Some modifications being tested also have an effect on the serum half-life of the antibody [50]. Controlling the pharmacokinetics may prove to be beneficial economically, with dosesparing, dose-saving, longer clinical effect, or allow mitigating toxicity with faster clearance. Concurrently, many other formats are being developed and evaluated [51]. Smaller molecules made of the variable region of antibodies may be used. The Fab consists in the variable region and its proximal constant domain of the heavy and light chains. It is monovalent and has a very short half-life in the circulation. To circumvent this problem, antibodies with a paratope selected to recognize two antigens have been developed and are currently in phase II trials [52]. Another way to ensure dual specificity is the use of scFv which may be covalently or Table 2 FDA approved antibodies. Antibody

Target

Tumors

Cetuximab Panitumumab Trastuzumab Pertuzumab Bevacizumab Ipilimumab Rituximab Ofatumumab Ibritumomab Tositumomab Alemtuzumab Brentuximab Gemtuzumab

EGFR EGFR HER2 HER2 VEGF CTLA-4 CD20 CD20 CD20 CD20 CD52 CD30 CD33

Colon flead and neck Colon Breast gastric Breast colon NSCLC glioblastoma kidney Melanoma NHL chronic lymphocytic leukemia Chronic lymphocytic leukemia Low grade or follicular B cell NHL Low grade or follicular B cell NHL Chronic Lymphocytic leukemia Hodgkin's lymphoma Acute myelogenous leukemia

5

non-covalently-linked heavy and light variable parts of an antibody [53]. This type of construct may be further modified to recognize two or more different antigenic structures as diabodies, tribodies etc. BiTE (Bi-specific T cell engager) and DART (dual affinity re-targeting) formats are currently being evaluated in the clinic [54,55]. They bridge T cells to cancer cells by recognizing the CD3 receptor on the former and the CD19 molecule on the lymphoma. Conversely, in some instances such as c-Met, it may be important to avoid cross-linking of the target receptor and single chain Ig is preferable [56]. At their inception, antibodies were described as the magic bullet capable of delivering payloads such as cytokines or cytotoxic molecules at specific sites. The time taken to decipher the proper chemistry to link antibodies to other molecules was longer than expected but AntibodyDrug-Conjugates (ADC) are now in the clinic with some products being commercialized [57]. The two products are conjugates between antibodies (brentuximab and trastuzumab) and cytotoxics (microtubule antagonists (monomethyl irostatin and maytansin, respectively)). The former is engineered as to deliver its payload after being cleaved by cathepsin B in the lysosome while the latter acts one most of the antibody has been degraded [58,59]. The clinical success of these ADCs leads to the development of numerous coupling and delivery approaches that are being evaluated [60]. 8. Checkpoint agents As mentioned above, many patients with a functional immune response against their cancer show little clinical benefit indicating that the growing cancer has evolved ways to evade the immune response. One approach taken to alleviate the immune system from this immunosuppression was to develop monoclonal antibodies which block regulators of the immune response. These checkpoints are used by the immune system to dampen the response once T cells have been stimulated. Two such molecules have been targeted by monoclonal antibodies and have generated highly encouraging clinical results. Ipilimumab is an antibody directed to CTLA-4 and is commercialized under the name of Yervoy. CTLA-4 is normally expressed by activated T cells with CD80 and CD86 expressed on antigen expressing cells and limits T cell response. By blocking this interaction, ipilimumab amplifies the immune response to the cancer. It also acts by killing regulatory T cells [61]. It was approved for the treatment of melanoma on the basis of clinical results in which 23% of patients receiving ipilimumab survived 3 years versus 10% [62]. The other checkpoint molecule to be targeted is called Programmed Death-1 (PD1) as well as its ligands PDL-1 and PDL-2. Antibodies blocking their interaction are currently being evaluated in the clinic [63]. Because CTLA-4 is expressed shortly after T cell stimulation and that PD-1's expression occurs later, it was estimated that the combination of both antibodies would have a greater benefit. This is seen in a recent clinical trial in which 53% of advanced melanoma patients responded to the treatment and 18% had a complete response. All responders had at least 80% reductions by week 12 and lasted more than one year [64]. The enthusiasm generated by these impressive results has motivated numerous clinical trials in which checkpoint blockers are being evaluated either alone or in combination and in numerous indications (Table 3). While the clinical benefit is undeniable, caution must be taken because serious side effects have been notice in these trials [65]. Nonetheless, these results are important steps in the fight against cancer and for the field of immunotherapy. 9. Calcium and immunotherapy Calcium signaling plays an important role in almost all biological processes including the immune response. The immune system undeniably plays a role in controlling cancer and recent clinical results show that we are getting closer to successfully use this powerful tool. However, it is relatively difficult to target a specific calcium-related mechanism

Please cite this article as: R. Rooke, Can calcium signaling be harnessed for cancer immunotherapy?, Biochim. Biophys. Acta (2014), http:// dx.doi.org/10.1016/j.bbamcr.2014.01.034

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Table 3 Current clinical development of PD-1/PD-1 L1 checkpoint blockers. Five other products have been identified but have not reached clinical stage. Source: Citeline. Drug

Company

Target

Cancer type

Status

Nivolumab BMS-936558 MDX-1106 ONO-4538

BMS/Ono

PD-1

Renal NSCLC Melanoma Prostate Colorectal Ovarian Solid CML Myeloma NHL Hodgkin's Liver Melanoma NSCLC Solid Breast Head and neck Renal Bladder Urethral Hematological NSCLC Melanoma Stomach Colorectal Renal Solid B-cell lymphoma Colorectal Melanoma NHL Breast Colorectal Renal NSCLC Melanoma Ovarian Stomach Pancreatic Melanoma Renal NSCLC Colorectal Solid

Phase III Phase III Phase III Phase II Phase II Phase II Phase 1 Phase 1 Phase 1 Phase 1 Phase 1 Phase 1 Phase II Phase II Phase 1 Phase 1 Phase 1 Phase 1 Phase 1 Phase 1 Preclinical Phase II Phase 1 Phase 1 Phase 1 Phase 1 Phase 1 Phase II Phase II Phase II Phase II Phase 1 Phase 1 Phase 1 Phase 1 Phase 1 Phase 1 Phase 1 Phase 1 Phase 1 Phase 1 Phase 1 Phase 1 Phase 1

Lambrolizumab MK-3475

RG-7446 MPDL-3280A

Merck

Roche

Pidilizumab CT-011

CureTech

MDX-1105 BMS-936559

BMS

PD-1

PD-1 LI

PD-1

PD-1 LI

MEDI-4736

AstraZeneka

PD-1 LI

MS B-0010718C

Merck KGaA

PD-1 LI

[3] [4] [5] [6]

[7]

[8]

[9]

[10]

[11] [12] [13]

[14] [15] [16] [17] [18]

[19]

[20]

without tampering with the calcium metabolism involved in other systems. As we are gaining knowledge on the interactions between the immune system and cancers, the steps in which calcium signaling are involved will become more obvious. One can therefore envisage using this additional tool to better modulate the immune response in favor of the patient. It is interesting to note that the T cell receptor-induced calcium response is reduced in PD-1 expressing cells [66]. Finally, one way by which calcium may be used is as a predictive or prognostic biomarker. The field remains unexplored to date.

[21] [22]

[23]

[24] [25]

References [26] [1] M.D. Vesely, M.H. Kershaw, R.D. Schreiber, M.J. Smyth, Natural innate and adaptive immunity to cancer, Annu. Rev. Immunol. 29 (2011) 235–271. [2] B.A. Fox, D.J. Schendel, L.H. Butterfield, S. Aamdal, J.P. Allison, P.A. Ascierto, M.B. Atkins, J. Bartunkova, L. Bergmann, N. Berinstein, C.C. Bonorino, E. Borden, J.L. Bramson, C.M. Britten, X. Cao, W.E. Carson, A.E. Chang, D. Characiejus, A.R. Choudhury, G. Coukos, T. de Gruijl, R.O. Dillman, H. Dolstra, G. Dranoff, L.G. Durrant, J.H. Finke, J. Galon, J.A. Gollob, C. Gouttefangeas, F. Grizzi, M. Guida, L. Hakansson, K. Hege, R.B. Herberman, F.S. Hodi, A. Hoos, C. Huber, P. Hwu, K. Imai, E.M. Jaffee, S. Janetzki, C.H. June, P. Kalinski, H.L. Kaufman, K. Kawakami, Y. Kawakami, U. Keilholtz, S.N. Khleif, R. Kiessling, B. Kotlan, G. Kroemer, R. Lapointe, H.I. Levitsky, M.T. Lotze, C. Maccalli, M. Maio, J.P. Marschner, M.J. Mastrangelo, G. Masucci, I. Melero, C. Melief, W.J. Murphy, B. Nelson, A. Nicolini, M.I. Nishimura, K. Odunsi, P.S. Ohashi, J. O'Donnell-Tormey, L.J. Old, C. Ottensmeier, M. Papamichail, G. Parmiani, G. Pawelec, E. Proietti, S. Qin, R. Rees, A. Ribas, R. Ridolfi, G. Ritter, L. Rivoltini, P.J. Romero, M.L. Salem, R.J. Scheper,

[27] [28] [29]

[30]

[31]

B. Seliger, P. Sharma, H. Shiku, H. Singh-Jasuja, W. Song, P.T. Straten, H. Tahara, Z. Tian, S.H. van Der Burg, P. von Hoegen, E. Wang, M.J. Welters, H. Winter, T. Withington, J.D. Wolchok, W. Xiao, L. Zitvogel, H. Zwierzina, F.M. Marincola, T.F. Gajewski, J.M. Wigginton, M.L. Disis, Defining the critical hurdles in cancer immunotherapy, J. Transl. Med. 9 (2011) 214. B. Rousseau, S. Champiat, D. Loirat, J. Arrondeau, N. Lemoine, J.C. Soria, Immunotherapies and targeted therapies in medical oncology, Bull. Cancer 101 (2014) 31–39. V. Robert, E. Triffaux, M. Savignac, L. Pelletier, Singularities of calcium signaling in effector T-lymphocytes, Biochim. Biophys. Acta 1833 (2013) 1595–1602. I.M. Ernst, R. Fliegert, A.H. Guse, Adenine dinucleotide second messengers and T-lymphocyte calcium signaling, Front. Immunol. 4 (2013) 259. R. Ramakrishnan, D.I. Gabrilovich, Novel mechanism of synergistic effects of conventional chemotherapy and immune therapy of cancer, Cancer Immunol. Immunother. 62 (2013) 405–410. S. Ladoire, D. Hannani, M. Vetizou, C. Locher, L. Aymeric, L. Apetoh, O. Kepp, G. Kroemer, F. Ghiringhelli, L. Zitvogel, Cell-death-associated molecular patterns as determinants of cancer immunogenicity, Antioxid. Redox Signal. (2013) in press, [Epub ahead of print]. O. Kepp, L. Menger, E. Vacchelli, C. Locher, S. Adjemian, T. Yamazaki, I. Martins, A.Q. Sukkurwala, M. Michaud, L. Senovilla, L. Galluzzi, G. Kroemer, L. Zitvogel, Crosstalk between ER stress and immunogenic cell death, Cytokine Growth Factor Rev. 24 (2013) 311–318. J. Galon, A. Costes, F. Sanchez-Cabo, A. Kirilovsky, B. Mlecnik, C. Lagorce-Pages, M. Tosolini, M. Camus, A. Berger, P. Wind, F. Zinzindohoue, P. Bruneval, P.H. Cugnenc, Z. Trajanoski, W.H. Fridman, F. Pages, Type, density, and location of immune cells within human colorectal tumors predict clinical outcome, Science 313 (2006) 1960–1964. W.B. Coley, The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigiosus), Proc. R. Soc. Med. 3 (1910) 1–48. J.A. Martinez-Pineiro, P. Muntanola, Nonspecific immunotherapy with BCG vaccine in bladder tumors: a preliminary report, Eur. Urol. 3 (1977) 11–22. E.J. Askeland, M.R. Newton, M.A. O'Donnell, Y. Luo, Bladder cancer immunotherapy: BCG and beyond, Adv. Urol. 2012 (2012) 181987. X. Yong, Y.F. Xiao, G. Luo, B. He, M.H. Lu, C.J. Hu, H. Guo, S.M. Yang, Strategies for enhancing vaccine-induced CTL antitumor immune responses, J. Biomed. Biotechnol. 2012 (2012) 605045. M.H. Kershaw, J.A. Westwood, P.K. Darcy, Gene-engineered T cells for cancer therapy, nature reviews, Cancer 13 (2013) 525–541. M. Kalos, C.H. June, Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology, Immunity 39 (2013) 49–60. M.X. Sliwkowski, I. Mellman, Antibody therapeutics in cancer, Science 341 (2013) 1192–1198. C. Kyi, M.A. Postow, Checkpoint blocking antibodies in cancer immunotherapy, FEBS Lett. 588 (2014) 368–376. H.M. Golomb, A. Jacobs, A. Fefer, H. Ozer, J. Thompson, C. Portlock, M. Ratain, D. Golde, J. Vardiman, J.S. Burke, et al., Alpha-2 interferon therapy of hairy-cell leukemia: a multicenter study of 64 patients, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 4 (1986) 900–905. J.A. Sparano, R.I. Fisher, M. Sunderland, K. Margolin, M.L. Ernest, M. Sznol, M.B. Atkins, J.P. Dutcher, K.C. Micetich, G.R. Weiss, et al., Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 11 (1993) 1969–1977. T.M. Law, R.J. Motzer, M. Mazumdar, K.W. Sell, P.J. Walther, M. O'Connell, A. Khan, V. Vlamis, N.J. Vogelzang, D.F. Bajorin, Phase III randomized trial of interleukin-2 with or without lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma, Cancer 76 (1995) 824–832. T. List, D. Neri, Immunocytokines: a review of molecules in clinical development for cancer therapy, Clin. Pharmacol. 5 (2013) 29–45. A. Barroso, E. Alpert, Diagnostic procedures in the evaluation of hepatic diseases. Functional evaluation: carcinoembryonic antigen (CEA) and alphafetoprotein (AFP) as tumor markers of the liver, Lab. Res. Methods Biol. Med. 7 (1983) 153–157. P. van der Bruggen, C. Traversari, P. Chomez, C. Lurquin, E. De Plaen, B. Van den Eynde, A. Knuth, T. Boon, A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma, Science 254 (1991) 1643–1647. N. Vigneron, V. Stroobant, B.J. Van den Eynde, P. van der Bruggen, Database of T cell-defined human tumor antigens: the 2013 update, Cancer Immun. 13 (2013) 15. C.N. Baxevanis, M. Papamichail, S.A. Perez, Therapeutic cancer vaccines: a long and winding road to success, Expert Rev. Vaccines 588 (2014) 131–144. R.S. Johnson, A.I. Walker, S.J. Ward, Cancer vaccines: will we ever learn? Expert. Rev. Anticancer. Ther. 9 (2009) 67–74. G.T. Motz, G. Coukos, Deciphering and reversing tumor immune suppression, Immunity 39 (2013) 61–73. A. Hoos, Evolution of end points for cancer immunotherapy trials, Ann. Oncol. 23 (Suppl. 8) (2012) viii47–viii52. A. Hoos, C.M. Britten, C. Huber, J. O'Donnell-Tormey, A methodological framework to enhance the clinical success of cancer immunotherapy, Nat. Biotechnol. 29 (2011) 867–870. A. Hoos, A.M. Eggermont, S. Janetzki, F.S. Hodi, R. Ibrahim, A. Anderson, R. Humphrey, B. Blumenstein, L. Old, J. Wolchok, Improved endpoints for cancer immunotherapy trials, J. Natl. Cancer Inst. 102 (2010) 1388–1397. C. Butts, M.A. Socinski, P.L. Mitchell, N. Thatcher, L. Havel, M. Krzakowski, S. Nawrocki, T.E. Ciuleanu, L. Bosquee, J.M. Trigo, A. Spira, L. Tremblay, J. Nyman, R. Ramlau, G. Wickart-Johansson, P. Ellis, O. Gladkov, J.R. Pereira, W.E. Eberhardt, C.

Please cite this article as: R. Rooke, Can calcium signaling be harnessed for cancer immunotherapy?, Biochim. Biophys. Acta (2014), http:// dx.doi.org/10.1016/j.bbamcr.2014.01.034

R. Rooke / Biochimica et Biophysica Acta xxx (2014) xxx–xxx

[32] [33]

[34]

[35] [36]

[37]

[38]

[39]

[40]

[41] [42] [43] [44]

[45] [46]

[47]

[48] [49]

[50] [51] [52]

Helwig, A. Schroder, F.A. Shepherd, Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial, Lancet Oncol. 15 (2014) 59–68. M. Ruella, M. Kalos, Adoptive immunotherapy for cancer, Immunol. Rev. 257 (2014) 14–38. N. Labarriere, A. Fortun, A. Bellec, A. Khammari, B. Dreno, S. Saiagh, F. Lang, A full GMP process to select and amplify epitope-specific T lymphocytes for adoptive immunotherapy of metastatic melanoma, Clin. Dev. Immunol. 2013 (2013) 932318. J. Weber, M. Atkins, P. Hwu, L. Radvanyi, M. Sznol, C. Yee, White paper on adoptive cell therapy for cancer with tumor-infiltrating lymphocytes: a report of the CTEP subcommittee on adoptive cell therapy, Clin. Cancer Res. 17 (2011) 1664–1673. M. Sadelain, R. Brentjens, I. Riviere, The basic principles of chimeric antigen receptor design, Cancer Discov. 3 (2013) 388–398. G. Gross, T. Waks, Z. Eshhar, Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity, Proc. Natl. Acad. Sci. U. S. A. 86 (1989) 10024–10028. D.S. Ritchie, P.J. Neeson, A. Khot, S. Peinert, T. Tai, K. Tainton, K. Chen, M. Shin, D.M. Wall, D. Honemann, P. Gambell, D.A. Westerman, J. Haurat, J.A. Westwood, A.M. Scott, L. Kravets, M. Dickinson, J.A. Trapani, M.J. Smyth, P.K. Darcy, M.H. Kershaw, H.M. Prince, Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia, Mol. Ther. 21 (2013) 2122–2129. J.H. Sampson, B.D. Choi, L. Sanchez-Perez, C.M. Suryadevara, D.J. Snyder, C.T. Flores, S.K. Nair, R.J. Schmittling, E.A. Reap, P.K. Norberg, J.E. Herndon II, C.T. Kuan, R.A. Morgan, S.A. Rosenberg, L.A. Johnson, EGFRvIII mCAR-modified T cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss, Clin. Cancer Res. (2013) in press [epub ahead of print]. R.A. Morgan, J.C. Yang, M. Kitano, M.E. Dudley, C.M. Laurencot, S.A. Rosenberg, Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2, Mol. Ther. 18 (2010) 843–851. E. Vacchelli, I. Vitale, A. Eggermont, W.H. Fridman, J. Fucikova, I. Cremer, J. Galon, E. Tartour, L. Zitvogel, G. Kroemer, L. Galluzzi, Trial watch: dendritic cell-based interventions for cancer therapy, Oncoimmunology 2 (2013) e25771. B. Frankenberger, D.J. Schendel, Third generation dendritic cell vaccines for tumor immunotherapy, Eur. J. Cell Biol. 91 (2012) 53–58. A. Nissim, Y. Chernajovsky, Historical development of monoclonal antibody therapeutics, Handb. Exp. Pharmacol. (2008) 3–18. J. Schwaber, E.P. Cohen, Human x mouse somatic cell hybrid clone secreting immunoglobulins of both parental types, Nature 244 (1973) 444–447. H.F. Sears, D. Herlyn, Z. Steplewski, H. Koprowski, Effects of monoclonal antibody immunotherapy on patients with gastrointestinal adenocarcinoma, J. Biol. Response Mod. 3 (1984) 138–150. L. Riechmann, M. Clark, H. Waldmann, G. Winter, Reshaping human antibodies for therapy, Nature 332 (1988) 323–327. N. Ferrara, K.J. Hillan, H.P. Gerber, W. Novotny, Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer, Nat. Rev. Drug Discov. 3 (2004) 391–400. S. Mathas, A. Rickers, K. Bommert, B. Dorken, M.Y. Mapara, Anti-CD20- and B-cell receptor-mediated apoptosis: evidence for shared intracellular signaling pathways, Cancer Res. 60 (2000) 7170–7176. R.A. Clynes, T.L. Towers, L.G. Presta, J.V. Ravetch, Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets, Nat. Med. 6 (2000) 443–446. S. Park, Z. Jiang, E.D. Mortenson, L. Deng, O. Radkevich-Brown, X. Yang, H. Sattar, Y. Wang, N.K. Brown, M. Greene, Y. Liu, J. Tang, S. Wang, Y.X. Fu, The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity, Cancer Cell 18 (2010) 160–170. T. Olafsen, Fc engineering: serum half-life modulation through FcRn binding, Methods Mol. Biol. 907 (2012) 537–556. A.L. Nelson, Antibody fragments: hope and hype, MAbs 2 (2010) 77–83. G. Schaefer, L. Haber, L.M. Crocker, S. Shia, L. Shao, D. Dowbenko, K. Totpal, A. Wong, C.V. Lee, S. Stawicki, R. Clark, C. Fields, G.D. Lewis Phillips, R.A. Prell, D.M. Danilenko,

[53]

[54]

[55]

[56]

[57] [58]

[59]

[60] [61]

[62]

[63] [64]

[65] [66]

7

Y. Franke, J.P. Stephan, J. Hwang, Y. Wu, J. Bostrom, M.X. Sliwkowski, G. Fuh, C. Eigenbrot, A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies, Cancer Cell 20 (2011) 472–486. R.A. Beckman, L.M. Weiner, H.M. Davis, Antibody constructs in cancer therapy: protein engineering strategies to improve exposure in solid tumors, Cancer 109 (2007) 170–179. P.A. Moore, W. Zhang, G.J. Rainey, S. Burke, H. Li, L. Huang, S. Gorlatov, M.C. Veri, S. Aggarwal, Y. Yang, K. Shah, L. Jin, S. Zhang, L. He, T. Zhang, V. Ciccarone, S. Koenig, E. Bonvini, S. Johnson, Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma, Blood 117 (2011) 4542–4551. G.S. Laszlo, C.J. Gudgeon, K.H. Harrington, J. Dell'aringa, K.J. Newhall, G.D. Means, A.M. Sinclair, R. Kischel, S.R. Frankel, R.B. Walter, Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML, Blood 123 (2014) 554–561. M. Merchant, X. Ma, H.R. Maun, Z. Zheng, J. Peng, M. Romero, A. Huang, N.Y. Yang, M. Nishimura, J. Greve, L. Santell, Y.W. Zhang, Y. Su, D.W. Kaufman, K.L. Billeci, E. Mai, B. Moffat, A. Lim, E.T. Duenas, H.S. Phillips, H. Xiang, J.C. Young, G.F. Vande Woude, M.S. Dennis, D.E. Reilly, R.H. Schwall, M.A. Starovasnik, R.A. Lazarus, D.G. Yansura, Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent, Proc. Natl. Acad. Sci. U. S. A. 110 (2013) E2987–E2996. C.R. Behrens, B. Liu, Methods for site-specific drug conjugation to antibodies, MAbs 6 (2013). N.M. Okeley, J.B. Miyamoto, X. Zhang, R.J. Sanderson, D.R. Benjamin, E.L. Sievers, P.D. Senter, S.C. Alley, Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug conjugate, Clin. Cancer Res. 16 (2010) 888–897. G.D. Lewis Phillips, G. Li, D.L. Dugger, L.M. Crocker, K.L. Parsons, E. Mai, W.A. Blattler, J.M. Lambert, R.V. Chari, R.J. Lutz, W.L. Wong, F.S. Jacobson, H. Koeppen, R.H. Schwall, S.R. Kenkare-Mitra, S.D. Spencer, M.X. Sliwkowski, Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate, Cancer Res. 68 (2008) 9280–9290. A. Beck, Review of antibody-drug conjugates, methods in molecular biology series: a book edited by Laurent Ducry, MAbs 6 (2013). T.R. Simpson, F. Li, W. Montalvo-Ortiz, M.A. Sepulveda, K. Bergerhoff, F. Arce, C. Roddie, J.Y. Henry, H. Yagita, J.D. Wolchok, K.S. Peggs, J.V. Ravetch, J.P. Allison, S.A. Quezada, Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma, J. Exp. Med. 210 (2013) 1695–1710. F.S. Hodi, S.J. O'Day, D.F. McDermott, R.W. Weber, J.A. Sosman, J.B. Haanen, R. Gonzalez, C. Robert, D. Schadendorf, J.C. Hassel, W. Akerley, A.J. van den Eertwegh, J. Lutzky, P. Lorigan, J.M. Vaubel, G.P. Linette, D. Hogg, C.H. Ottensmeier, C. Lebbe, C. Peschel, I. Quirt, J.I. Clark, J.D. Wolchok, J.S. Weber, J. Tian, M.J. Yellin, G.M. Nichol, A. Hoos, W.J. Urba, Improved survival with ipilimumab in patients with metastatic melanoma, N. Engl. J. Med. 363 (2010) 711–723. S.L. Topalian, C.G. Drake, D.M. Pardoll, Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity, Curr. Opin. Immunol. 24 (2012) 207–212. J.D. Wolchok, H. Kluger, M.K. Callahan, M.A. Postow, N.A. Rizvi, A.M. Lesokhin, N.H. Segal, C.E. Ariyan, R.A. Gordon, K. Reed, M.M. Burke, A. Caldwell, S.A. Kronenberg, B.U. Agunwamba, X. Zhang, I. Lowy, H.D. Inzunza, W. Feely, C.E. Horak, Q. Hong, A.J. Korman, J.M. Wigginton, A. Gupta, M. Sznol, Nivolumab plus ipilimumab in advanced melanoma, N. Engl. J. Med. 369 (2013) 122–133. D.B. Page, M.A. Postow, M.K. Callahan, J.P. Allison, J.D. Wolchok, Immune modulation in cancer with antibodies, Annu. Rev. Med. 65 (2014) 185–202. S.F. Wang, S. Fouquet, M. Chapon, H. Salmon, F. Regnier, K. Labroquere, C. Badoual, D. Damotte, P. Validire, E. Maubec, N.B. Delongchamps, A. Cazes, L. Gibault, M. Garcette, M.C. Dieu-Nosjean, M. Zerbib, M.F. Avril, A. Prevost-Blondel, C. Randriamampita, A. Trautmann, N. Bercovici, Early T cell signalling is reversibly altered in PD-1+ T lymphocytes infiltrating human tumors, PLoS One 6 (2011) e17621.

Please cite this article as: R. Rooke, Can calcium signaling be harnessed for cancer immunotherapy?, Biochim. Biophys. Acta (2014), http:// dx.doi.org/10.1016/j.bbamcr.2014.01.034

Can calcium signaling be harnessed for cancer immunotherapy?

Experimental evidence shows the importance of the immune system in controlling tumor appearance and growth. Immunotherapy is defined as the treatment ...
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