IMMUNO-ONCOLOGY COMES OF AGE
Immuno-oncology Comes of Age—Introduction
T
he history of cancer immunotherapy dates back to 1890 when Coley first demonstrated that bacterial products, he coined “Coley toxins,” could induce regression of established inoperable tumors. When Coley’s work was finally published in 1953,1 it sparked the beginning of cancer immunotherapy and led to the application of Bacillus Calmette-Guerin (BCG) for the treatment of solid tumors, such as bladder cancer, in the 1960s. Henceforth, research scientists have been striving to devise ways to reproducibly stimulate an effective anti-tumor immune response for the treatment of cancer. The next major milestones in immunotherapy came in the 1970s and 1980s with the discovery of cytokines such as interferon alpha (IFN-α) and interleukin-2 (IL-2), identification of the first tumor-associated antigens (TAAs), development of tumor-specific monoclonal antibodies (mAbs), and the first successful application of adoptive cell therapy (ACT) to treat cancer.2 Clinical studies demonstrated that stimulating the antitumor immune response with immunomodulatory cytokines such as IFN-α or IL-2 could mediate regression of established tumors.3,4 These data ultimately led to regulatory approval of IFN-α2 for hairy cell leukemia in 1986 and recombinant IL-2 (rIL-2) for the treatment of metastatic renal cell carcinoma in 1992 and metastatic melanoma in 1998. Among patients with advanced metastatic melanoma treated with highdose rIL-2, 5%– 10% experienced durable complete responses and many remained disease-free more than 20 years later.5 However, treatment with high-dose rIL2 did not improve overall survival and presents many challenges, including severe toxicity. Unfortunately, to this day, it remains unclear why a small percentage of patients benefit while the vast majority do not. No biomarker of response has ever been identified. During this time, landmark research was being conducted at the National Cancer Institute to isolate and characterize tumor-infiltrating lymphocytes (TILs), which could now be grown ex vivo with IL-2. The culmination of this research led to the Financial support for this supplement was provided by an unrestricted educational grant from Merck & Co., Inc. Conflict of interest statement: Dr Weber has received honoraria or consulting fees from Bristol-Myers Squibb, Genentech, and Merck. 0093-7754/ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2014.09.002
successful identification of TAAs and tumor-specific antigens (TSAs) and to the first demonstration in 1985 that ACT using tumor-specific TILs could induce tumor regression in patients with advanced cancer.4 The characterization of TAAs and TSAs spurred the development of therapeutic cancer vaccines using peptides, whole proteins, dendritic cells (DCs), recombinant viruses, whole cells, and plasmid DNA. However, with few exceptions these vaccine strategies have failed. The greatest challenge facing vaccines and immunotherapy in general has been the immunosuppressive tumor microenvironment. This hurdle can be overcome to some extent by adoptive transfer of tumor-specific TILs, which can be expanded ex vivo and reinfused in large numbers (up to 1011 cells). When preceded by lymphodepletion with chemotherapy or radiation to eliminate regulatory T cells and myeloid-derived suppressor cells, ACT has been shown to mediate reproducible and durable complete tumor regression in up to 20% of heavily pretreated patients with melanoma.6–9 Although traditional patient-specific ACT is cumbersome and costly, efforts to make this approach more widely applicable are ongoing. Tremendous progress has been made in the past two decades with regard to understanding the complex interactions between tumors and the immune system and developing innovative ways to manipulate the antitumor immune response.10 As a result, immunotherapy has achieved an important milestone in recent years, improving overall survival in patients with advanced metastatic disease (specifically melanoma and prostate cancer). In part, this achievement comes from understanding how tumor cells exploit immune checkpoint receptors, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) or programmed cell death 1 (PD-1) expressed on activated T cells, to suppress the anti-tumor immune response. Antibodies against CTLA-4 and PD-1 can release the brakes on the immune response and allow T cells to expand, produce cytokines, and carry out their normal effector functions. However, this also can lead to autoimmune reactions that range from bothersome to life-threatening. This achievement also comes from designing better DCbased vaccines that take advantage of decades of research to understand how to supercharge DCs to elicit an effective and sustained anti-tumor immune response. The recent success in melanoma and
Seminars in Oncology, Vol 41, No 5, Suppl 5, October 2014, pp S1-S2
S1
S2
Jeffrey S. Weber
prostate cancer has reignited the hope that immunotherapy could be an effective strategy for a wide range of solid tumors. The growth of clinical research in this area has been impressive, and everyone is working to take advantage of our improved understanding of tumor immunology to overcome the challenges that have limited the potential of cancer immunotherapy in the past. In this supplement, Mary (Nora) Disis, MD (Tumor Vaccine Group, University of Washington, Seattle, WA), first discusses the mechanism of action of the various approaches to immunotherapy. Thereafter, Jeffrey Weber, MD, PhD (H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL), provides a clinical perspective on where we are today in the development of cancer immunotherapy with a focus on immune checkpoint inhibitors and therapeutic vaccines. Finally, Brian Rini, MD (Cleveland Clinic, Cleveland, OH), discusses future approaches in cancer immunotherapy with a focus on combination strategies.
Jeffrey S. Weber, MD, PhD H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL Guest Editor
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REFERENCES 1. Nauts HC, Fowler GA, Bogatko FH. A review of the influence of bacterial infection and of bacterial products (Coley’s toxins) on malignant tumors in man; a critical analysis of 30 inoperable cases treated by Coley’s mixed toxins, in which diagnosis was
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confirmed by microscopic examination selected for special study. Acta Med Scand Suppl. 1953;276:1–103. Kirkwood JM, Butterfield LH, Tarhini AA, Zarour H, Kalinski P, Ferrone S. Immunotherapy of cancer in 2012. CA Cancer J Clin. 2012;62:309–35. Kirkwood JM, Ernstoff MS. Interferons in the treatment of human cancer. J Clin Oncol. 1984;2:336–52. Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med. 1985;313:1485–92. Smith FO, Downey SG, Klapper JA, Yang JC, Sherry RM, Royal RE, et al. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin Cancer Res. 2008;14:5610–8. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002;298: 850–4. Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26:5233–9. Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17:4550–7. Wrzesinski C, Paulos CM, Kaiser A, Muranski P, Palmer DC, Gattinoni L, et al. Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. J Immunother. 2010;33:1–7. Eggermont A, Finn O. Advances in immuno-oncology. Foreword. Ann Oncol. 2012;23(Suppl 8):viii5.
Immuno-oncology Comes of Age—Introduction
T
he history of cancer immunotherapy dates back to 1890 when Coley first demonstrated that bacterial products, he coined “Coley toxins,” could induce regression of established inoperable tumors. When Coley’s work was finally published in 1953,1 it sparked the beginning of cancer immunotherapy and led to the application of Bacillus Calmette-Guerin (BCG) for the treatment of solid tumors, such as bladder cancer, in the 1960s. Henceforth, research scientists have been striving to devise ways to reproducibly stimulate an effective anti-tumor immune response for the treatment of cancer. The next major milestones in immunotherapy came in the 1970s and 1980s with the discovery of cytokines such as interferon alpha (IFN-α) and interleukin-2 (IL-2), identification of the first tumor-associated antigens (TAAs), development of tumor-specific monoclonal antibodies (mAbs), and the first successful application of adoptive cell therapy (ACT) to treat cancer.2 Clinical studies demonstrated that stimulating the antitumor immune response with immunomodulatory cytokines such as IFN-α or IL-2 could mediate regression of established tumors.3,4 These data ultimately led to regulatory approval of IFN-α2 for hairy cell leukemia in 1986 and recombinant IL-2 (rIL-2) for the treatment of metastatic renal cell carcinoma in 1992 and metastatic melanoma in 1998. Among patients with advanced metastatic melanoma treated with highdose rIL-2, 5%– 10% experienced durable complete responses and many remained disease-free more than 20 years later.5 However, treatment with high-dose rIL2 did not improve overall survival and presents many challenges, including severe toxicity. Unfortunately, to this day, it remains unclear why a small percentage of patients benefit while the vast majority do not. No biomarker of response has ever been identified. During this time, landmark research was being conducted at the National Cancer Institute to isolate and characterize tumor-infiltrating lymphocytes (TILs), which could now be grown ex vivo with IL-2. The culmination of this research led to the Financial support for this supplement was provided by an unrestricted educational grant from Merck & Co., Inc. Conflict of interest statement: Dr Weber has received honoraria or consulting fees from Bristol-Myers Squibb, Genentech, and Merck. 0093-7754/ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2014.09.002
successful identification of TAAs and tumor-specific antigens (TSAs) and to the first demonstration in 1985 that ACT using tumor-specific TILs could induce tumor regression in patients with advanced cancer.4 The characterization of TAAs and TSAs spurred the development of therapeutic cancer vaccines using peptides, whole proteins, dendritic cells (DCs), recombinant viruses, whole cells, and plasmid DNA. However, with few exceptions these vaccine strategies have failed. The greatest challenge facing vaccines and immunotherapy in general has been the immunosuppressive tumor microenvironment. This hurdle can be overcome to some extent by adoptive transfer of tumor-specific TILs, which can be expanded ex vivo and reinfused in large numbers (up to 1011 cells). When preceded by lymphodepletion with chemotherapy or radiation to eliminate regulatory T cells and myeloid-derived suppressor cells, ACT has been shown to mediate reproducible and durable complete tumor regression in up to 20% of heavily pretreated patients with melanoma.6–9 Although traditional patient-specific ACT is cumbersome and costly, efforts to make this approach more widely applicable are ongoing. Tremendous progress has been made in the past two decades with regard to understanding the complex interactions between tumors and the immune system and developing innovative ways to manipulate the antitumor immune response.10 As a result, immunotherapy has achieved an important milestone in recent years, improving overall survival in patients with advanced metastatic disease (specifically melanoma and prostate cancer). In part, this achievement comes from understanding how tumor cells exploit immune checkpoint receptors, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) or programmed cell death 1 (PD-1) expressed on activated T cells, to suppress the anti-tumor immune response. Antibodies against CTLA-4 and PD-1 can release the brakes on the immune response and allow T cells to expand, produce cytokines, and carry out their normal effector functions. However, this also can lead to autoimmune reactions that range from bothersome to life-threatening. This achievement also comes from designing better DCbased vaccines that take advantage of decades of research to understand how to supercharge DCs to elicit an effective and sustained anti-tumor immune response. The recent success in melanoma and
Seminars in Oncology, Vol 41, No 5, Suppl 5, October 2014, pp S1-S2
S1
S2
Jeffrey S. Weber
prostate cancer has reignited the hope that immunotherapy could be an effective strategy for a wide range of solid tumors. The growth of clinical research in this area has been impressive, and everyone is working to take advantage of our improved understanding of tumor immunology to overcome the challenges that have limited the potential of cancer immunotherapy in the past. In this supplement, Mary (Nora) Disis, MD (Tumor Vaccine Group, University of Washington, Seattle, WA), first discusses the mechanism of action of the various approaches to immunotherapy. Thereafter, Jeffrey Weber, MD, PhD (H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL), provides a clinical perspective on where we are today in the development of cancer immunotherapy with a focus on immune checkpoint inhibitors and therapeutic vaccines. Finally, Brian Rini, MD (Cleveland Clinic, Cleveland, OH), discusses future approaches in cancer immunotherapy with a focus on combination strategies.
Jeffrey S. Weber, MD, PhD H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL Guest Editor
2.
3. 4.
5.
6.
7.
8.
9.
REFERENCES 1. Nauts HC, Fowler GA, Bogatko FH. A review of the influence of bacterial infection and of bacterial products (Coley’s toxins) on malignant tumors in man; a critical analysis of 30 inoperable cases treated by Coley’s mixed toxins, in which diagnosis was
10.
confirmed by microscopic examination selected for special study. Acta Med Scand Suppl. 1953;276:1–103. Kirkwood JM, Butterfield LH, Tarhini AA, Zarour H, Kalinski P, Ferrone S. Immunotherapy of cancer in 2012. CA Cancer J Clin. 2012;62:309–35. Kirkwood JM, Ernstoff MS. Interferons in the treatment of human cancer. J Clin Oncol. 1984;2:336–52. Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med. 1985;313:1485–92. Smith FO, Downey SG, Klapper JA, Yang JC, Sherry RM, Royal RE, et al. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin Cancer Res. 2008;14:5610–8. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002;298: 850–4. Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26:5233–9. Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17:4550–7. Wrzesinski C, Paulos CM, Kaiser A, Muranski P, Palmer DC, Gattinoni L, et al. Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. J Immunother. 2010;33:1–7. Eggermont A, Finn O. Advances in immuno-oncology. Foreword. Ann Oncol. 2012;23(Suppl 8):viii5.
