November 2012, Vol 1, No 5
The Cancer Immunotherapy Trials Network: A National Strategy for the Development and Implementation of Immunotherapy for the Treatment of CancerImmunotherapy
- The clinical development of immunotherapy has lagged behind the theoretical and preclinical models, but the potential for durable therapeutic responses has been recognized for many years
- The lack of widespread clinical expertise with immunotherapy presents a challenge for fully realizing the therapeutic opportunities of emerging immunotherapeutic strategies
- The Cancer Immunotherapy Trials Network was established to address these concerns and promote the rapid development of new immunotherapy agents and combination therapy using an integrated national network
Tumor immunotherapy is a modality of cancer therapy that utilizes the immune system to recognize and eradicate cancer.1-5 The potential for tumor immunotherapy has been recognized for over a century after William Coley’s initial observation, “at the end of two weeks [since vaccination with erysipelas] the tumor in the neck had disappeared.”1 The work of Burnet and Thomas in the 1950s further established that the immune system was capable of immune surveillance and provided the foundation for understanding the nature of tumor rejection antigens. In the 1980s such rejection antigens were indeed identified in cancer cells, most notably in melanoma. These discoveries paved the way for vaccine development and provided a basic foundation for understanding how the immune system can be used for therapeutic purposes in cancer.
The clinical development of immunotherapy has lagged behind the theoretical and preclinical models, but the potential for durable therapeutic responses has been recognized for many years. The first major success was the use of allogeneic hematopoietic cell transplantation for leukemia, which was first performed in 1956.6 The use of nonspecific agents followed, including approval of Bacillus Calmette-Guérin for superficial bladder cancer, the cytokine interferon-alpha for treatment of hairy cell leukemia and adjuvant therapy of stage III melanoma, and interleukin-2 for treatment of metastatic renal cell carcinoma and melanoma. Monoclonal antibodies targeting surface molecules on tumor cells mediate antitumor activity, at least in part, through immune mechanisms, and several approved agents are current standard of care, most notably rituximab, which targets CD20 and is approved for the treatment of patients with non-Hodgkin lymphoma,7 and trastuzumab, which targets HER2/neu and is approved for the treatment of HER2-expressing metastatic breast cancer.1
The development of antigen-specific immunotherapy remained a more elusive goal, and caution was warranted based on significant toxicity reported with an anti-CD28 monoclonal antibody.2,8-12 Despite these challenges, the field has been re-energized with the approval of sipuleucel-T, an antigen-specific vaccine for prostate cancer in 2010, and ipilimumab, an anticytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibody for metastatic melanoma in 2011.4,5 These agents, while first in class, have ushered in a new era of tumor immunotherapy and have highlighted the potential of such treatment in patients with advanced cancer. The unique toxicity profiles of these agents, the need for more appropriate clinical end points based on the mechanism of action of immunotherapy agents, and the lack of widespread clinical expertise with immunotherapy presents a challenge for fully realizing the therapeutic opportunities of emerging immunotherapeutic strategies. Most importantly, the major barrier to the development of effective immunotherapy is the lack of broad availability of already invented immunotherapy agents with known and profound ability to augment immune responses. Agents from the interleukin (IL) family, such as IL-15 and IL-7, have high potential to benefit cancer patients but are not broadly available for testing. The Cancer Immunotherapy Trials Network (CITN) was established to address these concerns and promote the rapid development of new immunotherapy agents and combination therapy using an integrated national network.
Sipuleucel-T and Ipilimumab as Paradigms
Sipuleucel-T and ipilimumab highlight several important features of modern tumor immunotherapy. Sipuleucel-T is an antigen-specific vaccine with limited side effects, both attractive pharmacologic features, but it is associated with limited clinical efficacy. In contrast, ipilimumab is not antigen specific and has significant toxicity requiring close clinical monitoring, but it may be associated with significant clinical benefit. The characteristics of these agents will be briefly discussed.
Sipuleucel-T is composed of autologous peripheral blood mononuclear cells, including dendritic cells, an immune-stimulating cytokine (granulocyte-macrophage colony-stimulating factor, GM-CSF), and prostatic acid phosphatase (PAP), a prostate-associated tumor antigen.4 The cells are extracted from patients through leukapheresis and require ex vivo loading of the PAP and GM-CSF, transport back to the clinic, and IV infusion into patients. In the pivotal randomized phase 3 trial, vaccination improved median survival by 4.1 months in patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer.4 This was the first vaccine to be approved in the United States for the treatment of established cancer utilizing an antigen-specific target. Vaccination is generally well tolerated, but challenges with autologous cell collection and viability, ex vivo manipulation and regulatory requirements, and the lack of a clear correlation between survival and induction of PAP-specific T-cell immunity suggest that further studies are needed to optimize this form of immunotherapy. Because clinical development of sipuleucel-T for FDA approval began in 1997, the formulation and regimen of sipuleucel-T have remained unchanged for almost 15 years. Given the advances made in immunology and immunotherapy in the past decade and a half, it is axiomatic that regimens based on current immunologic science would provide higher and longer-lasting immune responses (ie, greater areas under the curve) and, in the case of sipuleucel-T, enhanced patient benefit. The question remains, “Which strategies are most likely to be effective and the most ripe for testing?” Agents such as IL-15, IL-7, anti–CTLA-4, and anti–PD-1 (programmed death 1) are among the priority agents being tested by the CITN and others that are likely to increase the efficacy of sipuleucel-T.
CTLA-4 is an inhibitory checkpoint receptor expressed on the surface of T cells, where it serves to inhibit T-cell activation and helps regulate the balance between immune activation and tolerance.13-15 T-cell function is regulated by a series of signals typically provided by antigen-presenting cells.16,17 In preclinical studies, the addition of an antagonist CTLA-4 monoclonal antibody with a specific vaccine was shown to induce antigen-specific T-cell activation and mediate rejection of B16 melanoma in mice.18 Ipilimumab is a humanized anti–CTLA-4 monoclonal antibody and has demonstrated therapeutic benefit in patients with metastatic melanoma.19-21 In a dose-finding trial, objective responses were seen in 11.1% of patients at the 10-mg/kg dose and in 4.2% at the 3-mg/kg dose, with no responses at the lower dose.19 The early studies of ipilimumab also identified a unique toxicity profile characterized by autoimmune events, including dermatitis, colitis, hepatitis, endocrinopathies, and neuritis.22-24 Mortality related to bowel perforation was reported in less than 2% of patients in early studies before the development of autoimmune toxicity was recognized. The autoimmune side effects are manageable with early use of low-dose steroids and, rarely, more intensive immunosuppressive treatment.24 The pivotal phase 3 clinical trial was a prospective, randomized, double-blind study of 676 HLA-A2 patients with previously treated metastatic melanoma.25 Patients treated with ipilimumab demonstrated an overall survival benefit of 10 months compared with 6.4 months in the vaccine-alone arm.25 A subsequent trial in treatment-naive metastatic melanoma patients demonstrated that overall survival was significantly prolonged to 11.2 months in the ipilimumab-treated patients compared with 9.1 months in dacarbazine-treated patients. A survival effect persisted at 3 years, with 20.8% alive in the ipilimumab/dacarbazine-treated arm compared with 12.2% in the dacarbazine-alone arm (hazard ratio for death, 0.72; P<.001).26
An interesting finding in both phase 3 ipilimumab studies was the lack of improvement in progression-free survival, suggesting that the immune response is slow to develop and can result in a delayed therapeutic response. Indeed, studies have shown that responses may be delayed for several months, and this has led to a new set of clinical immune response guidelines for clinical monitoring of patients on immunotherapy studies.27,28 These guidelines require further validation, and this may be possible through the CITN.
PD-1 is another T-cell coinhibitory receptor that binds to the PD-1 and PD-2 ligands (PD-L1, PD-L2) on antigen-presenting cells and suppresses T-cell activation. PD-1 is highly expressed on both activated and exhausted T cells following exposure to chronic antigen, while PD-L1 is expressed directly on cancer cells in a number of different tumors, including melanoma, renal cell, colorectal, ovarian, and non–small cell lung cancer (NSCLC).29-39 A humanized antibody to PD-1 has been evaluated in patients with previously treated solid tumors, with objective responses reported in patients with colorectal cancer, melanoma, and NSCLC.40,41 More recently, a phase 1 clinical trial using an anti–PD-L1 monoclonal antibody in a dose-escalation design ranging from 0.3 mg/kg to 10 mg/kg was conducted in patients with metastatic cancer, with objective clinical responses observed in 9 of 52 evaluable melanoma, 2 of 17 renal cell carcinoma, 5 of 49 NSCLC, and 1 of 17 ovarian cancer patients.42
These clinical data are encouraging, and there are numerous other agents that have shown preclinical potential or early-stage clinical evidence of therapeutic effectiveness. For example, novel cytokines in development include IL-15, IL-18, IL-21, and new immune checkpoint-targeted monoclonal antibodies against OX40, 4-1BB, GITR, and CD27 are in development. Further, there is evidence that blockade of CTLA-4 and PD-1 can act synergistically against the murine B16 melanoma, providing evidence that combination immunotherapy should be pursued in the clinic.43 Because of the availability of these new agents, coupled with the cost of drug development and the need for more appropriate clinical trial designs that can better capture the impact of immunotherapy drugs, a model for prioritization of agents and trial design is needed to ensure that the full impact of tumor immunotherapy can be realized for patients with cancer.
Mission of the CITN
The goal of the CITN is to facilitate broad availability of multiple immunotherapy agents with defined biologic function for cancer therapy. The CITN is selecting, designing, and conducting early-phase trials with highly promising immunotherapy agents and provides a platform for high-quality immune monitoring and biomarker studies essential to inform subsequent development pathways leading to the commercialization of these agents for treating patients with cancer. The work performed through the network is expediting regulatory approval of cancer immunotherapy.
CITN members help design novel early-phase trials developing strategies and biomarkers that inform phase 3 pivotal trials. The CITN will implement and complete complex multicomponent trials that facilitate subsequent development pathways, particularly of agents in combination. The CITN will also provide high-quality immune response and biomarker data that elucidate mechanism of response and inform design of subsequent trials.
The CITN is a collaborative research project established by and operating under a grant from the National Cancer Institute (NCI) and awarded to the Central Operating and Statistical Center (COSC) at the Fred Hutchinson Cancer Research Center (FHCRC). The COSC provides overall leadership, organizational infrastructure, and statistical and protocol coordination support. A competitive grant process was used by the NCI to select 28 participating sites across the United States and Canada. Input from NCI and industry partners is also utilized to foster the identification of promising agents and integration to promote combination strategies.
Organizational Structure of the CITN
The organization model of the CITN is an interactive, inclusive organization whose members and collaborators strive toward common goals. The overall organizational structure and governance of the CITN is outlined in the Figure. The CITN, collaborating with the NCI, industry, and various disease-oriented and nonprofit foundations, uses the collective experience and wisdom in the field to prioritize and develop optimal trials in a synergistic fashion that will be more informative than those performed by scientists and companies working in isolation. The NCI, FHCRC, and member institutions each contributes resources to the CITN. Within the NCI, the Biological Resources Branch, Biometrics Research Branch, and Cancer Therapy Evaluation Program (CTEP) provide support to CITN trials. CTEP plays an important role in study regulatory and data management through the Cancer Trials Support Unit, site monitoring and auditing through the Clinical Trials Monitoring Branch, and application for investigational new drugs through the Regulatory Affairs Branch. Three core facilities are provided by FHCRC, specifically in collaboration with the HIV Vaccine Trials Network (regulatory and trial operations support), the Statistical Center for HIV/AIDS Research & Prevention (supporting statistical design and analysis), and a joint collaboration with FHCRC and the University of Washington (scientific leadership and laboratory management). Each member site provides guidance in trial design, patient enrollment, safety reporting, protocol compliance, as well as biospecimen collection and laboratory analysis. To foster new cancer immunotherapy clinical trials, the CITN works closely with corporate/pharmaceutical entities to identify and select agents for investigation and to obtain access to these therapeutics. Given the complexity of trial implementation, the CITN partners with foundations and nonprofit organizations with expertise in a specific disease or therapeutic area.
Leadership of the CITN comprises the Executive Committee including the COSC principal investigator (PI), 3 PIs from member sites, an administrative director, laboratory director, and NCI program officer (Figure). At the level of an identified drug and selected protocol, the CITN organizes Concept Working Groups, which have the responsibility of determining the study design and final clinical trial protocol. The Working Group includes a chair and cochairs from member sites, consultants familiar with the disease area or the therapeutic, a statistician, patient advocate, protocol development manager, immune monitoring core representative, CTEP/NCI member, and an industry representative, depending on the agent and industry interest in contributing.
Processes of the CITN
The list of priority agents to be investigated by the CITN resulted from 3 prior NCI workshops and feedback from over 80 leaders providing clinical and scientific expertise. The first workshop, Immunotherapy Agent Workshop, ranked the top 20 agents from 126 suggestions with known substantial immunologic activity that have not been adequately tested in cancer patients.44
Shortly thereafter, the Cancer Antigen Prioritization Project ranked 75 target cancer antigens according to predetermined and predefined characteristics to focus on the 6 most promising.45 Finally, given the potential for combining agents, an Immune Response Modifier Pathway Working Group developed criteria to structure the combination of immunopotentiating agents with vaccines in clinical trials.46 The final list of top agents to bring to patients in clinical trials is shown in Table 1 and includes T-cell growth factors (IL-7 and IL-15), dendritic cell activators (anti-CD40), inhibitors of T-cell checkpoint blockade (anti–PD-1), dendritic cell growth factors (Flt3L), vaccine adjuvants (IL-12), and T-cell stimulators (4-1BB).
Clinical trials entering the CITN are selected by a peer review process. Trials can be submitted from both academia and industry. A Letter of Intent is reviewed by the CITN Executive Committee and either rejected or forwarded to the CITN Steering Committee for further review. The Steering Committee is composed of a subgroup of CITN site investigators. Members of the Steering Committee serve for 3-year terms. The committee will approve or disapprove the proposal and assign the concept a priority. High-priority concepts move forward in the system, while approved but lower-priority concepts may be held while an alternate funding strategy is developed. Once a concept is deemed high priority, a lead investigator is identified and a Working Group is formed. This Working Group fully develops the protocol. Simultaneously, the Correlative Sciences Committee works with the protocol group to develop the laboratory analysis to support the study. Once completed, the protocol moves forward for institutional and CTEP approval.
During the review process, the CITN Executive Committee determines the source of and obtains the proposed immunotherapy agent(s), discusses with member sites and determines the financial expense of the trial, and reviews the trial implementation/start-up steps needed at participating institutions. Given the limited per patient budget of the CITN, depending on the expense of the particular trial, secondary sources of funding are obtained. Prior to finalization and CTEP approval, pharmaceutical/industrial agreements are reached in order to guarantee drug supply.
A key component of the CITN is a central immunologic monitoring laboratory and a CITN member laboratory network. The central laboratory assures adequate shipping and processing of samples from the studies and manages the assays that will be performed by the central laboratory or other laboratories in the network. Within the network lies significant expertise in basic immunologic monitoring, flow cytometry, analysis of the tumor microenvironment, assessment of circulating tumor cells, and other specialized assays. The laboratory analyses are prioritized into primary and secondary assays. Primary assays are those that are performed during the course of the study, and secondary assays are those that may be performed once the study has been completed. Prioritization of the analysis maximizes the collection of useful information in the most efficient manner possible.
Member Sites of the CITN
The CITN selected member sites through a competitive National Institutes of Health grant process and selection criteria, including basic tumor immunotherapy experience at the site, willingness to participate in proposed clinical trials, availability of clinical trial infrastructure, and ability to participate in establishing validation standards or collect biospecimen data for inclusion in immune monitoring and biomarker correlative studies. Member sites were asked to select a PI for coordinating the activities at each site and to participate in the executive committee. The member sites are located throughout the continental United States and Canada, assuring patient access for pivotal clinical trials. The member sites and PI contact information is listed in Table 2. Further information and updates are available on the CITN Web site at www.CITNinfo.org.
How to Refer to the CITN
Clinical trials initiated through the CITN will be listed on www.clinicaltrials.gov, at member institutions’ trial registries, and at www.CITNinfo.org. Study contacts, including study PI or trial coordinator will be listed for each participating institution in a CITN organized clinical trial. Patients are encouraged to speak with their primary oncologist to discuss their interest in clinical trials, including CITN and non-CITN developed trials. Risks and benefits of a clinical trial and alternative treatment options should be discussed when considering a patient’s next therapy. Referring physicians should contact a local PI or co-PI based on the specific trial of interest. Contact information, similarly, can be obtained at the sites listed above.
Pharmaceutical and industry representatives with interest in collaboration should contact Martin A. “Mac” Cheever, MD, the principal investigator of the CITN based at the FHCRC.
Cancer immunotherapy has come of age, and the promise of improved survival by targeting the immune response against cancer has been demonstrated with several agents, including sipuleucel-T and ipilimumab. However, this marks only the beginning of an era of immunotherapy that faces significant challenges in selection of agents, design of clinical trials, ensuring availability of novel therapies, and developing processes for working through the complex regulatory, intellectual property, and financial challenges for combining immunotherapy agents. The NCI has established the CITN as a means to prioritize immunotherapy agents and combinations, gain access to high-priority agents, develop clinical trial designs that are appropriate for detecting therapeutic effectiveness, validating and incorporating correlative immune monitoring and biomarker assays into clinical trials, and implementing a national network for patient participation in pivotal tumor immunotherapy trials. The CITN provides a uniquely organized effort to conduct early-phase trials, with a focus on trials likely to achieve the quickest route to proof of concept, demonstration of patient benefit, and provide a pathway to regulatory approval.
By accelerating ongoing interactions between CITN investigators, industry, foundations, and nonprofit entities, the CITN strives to have many immunotherapy agents with defined biologic function broadly available for rapid clinical trial evaluation. The CITN will play a significant role in firmly establishing the effectiveness of tumor immunotherapy and defining the clinical application of immunotherapy as a standard treatment for patients with cancer.
The authors would like to acknowledge Dr “Mac” Cheever for useful discussions and guidance in the manuscript preparation, and Judith Kaiser for providing investigator contact information.
- Krieg AM. Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov. 2006;5:471-484.
- Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480-489.
- Topalian SL, Weiner GJ, Pardoll DM. Cancer immunotherapy comes of age. J Clin Oncol. 2011;29:4828-4836.
- Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
- Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.
- Thomas ED, Lochte HL Jr, Lu WC, et al. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N Engl J Med. 1957;257:491-496.
- Maloney DG. Immunotherapy for non-Hodgkin’s lymphoma: monoclonal antibodies and vaccines. J Clin Oncol. 2005;23:6421-6428.
- Houot R, Levy R. Idiotype vaccination for lymphoma: moving towards optimisation. Leuk Lymphoma. 2009;50:1-2.
- Houot R, Levy R. Vaccines for lymphomas: idiotype vaccines and beyond. Blood Rev. 2009;23:137-142.
- Peled N, Oton AB, Hirsch FR, et al. MAGE A3 antigen-specific cancer immunotherapeutic. Immunotherapy. 2009;1:19-25.
- Korman AJ, Peggs KS, Allison JP. Checkpoint blockade in cancer immunotherapy. Adv Immunol. 2006;90:297-339.
- Stebbings R, Findlay L, Edwards C, et al. “Cytokine storm” in the phase I trial of monoclonal antibody TGN1412: better understanding the causes to improve preclinical testing of immunotherapeutics. J Immunol. 2007;179:3325-3331.
- Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270:985-988.
- Tivol EA, Borriello F, Schweitzer AN, et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3:541-547.
- Chambers CA, Sullivan TJ, Allison JP. Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity. 1997;7:885-895.
- Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23:515-548.
- Salama AK, Hodi FS. Cytotoxic T-lymphocyte-associated antigen-4. Clin Cancer Res. 2011;17:4622-4628.
- van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med. 1999;190:355-366.
- Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155-164.
- O’Day SJ, Maio M, Chiarion-Seleni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010;21:1712-1717.
- 21. Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15:5591-5598.
- Robinson MR, Chan CC, Yang JC, et al. Cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma: a new cause of uveitis. J Immunother. 2004;27:478-479.
- Blansfield JA, Beck KE, Tran K, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother. 2005;28:593-598.
- Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003; 100:8372-8377.
- Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363: 711-723.
- Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364: 2517-2526.
- Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412-7420.
- Hoos A, Eggermont AM, Janetzki S, et al. Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst. 2010;102:1388-1397.
- Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027-1034.
- Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682-687.
- Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 2005;65:1089-1096.
- Sheppard KA, Fitz LJ, Lee JM, et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004;574:37-41.
- Okazaki T, Maeda A, Nishimura H, et al. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A. 2001;98:13866-13871.
- Yamazaki T, Akiba H, Iwai H, et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol. 2002;169:5538-5545.
- Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99:12293-12297.
- Hino R, Kabashima K, Kato Y, et al. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 2010;116:1757-1766.
- He YF, Zhang GM, Wang XH, et al. Blocking programmed death-1 ligand-PD-1 interactions by local gene therapy results in enhancement of antitumor effect of secondary lymphoid tissue chemokine. J Immunol. 2004;173:4919-4928.
- Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 2003;63:6501-6505.
- Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19:813-824.
- Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167-3175.
- Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.
- Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012; 366:2455-2465.
- Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107:4275-4280.
- National Cancer Institute Immunotherapy Agent Workshop. https://dcb.nci.nih.gov/Reports/Pages/immunotherapyagentworkshop.aspx. Accessed September 20, 2012.
- Cheever MA, Allison JP, Ferris AS, et al. The prioritization of cancer antigens: a National Cancer Institute pilot project for the acceleration of translational research. Clin Cancer Res. 2009;15:5323-5337.
- Cheever MA, Matrisian LM. Report of the Immune Response Modifier Pathway Prioritization Working Group (IRMP WG), November 2009. http://deainfo.nci.nih.gov/advisory/ctac/workgroup/ctacsupmat.htm. Accessed September 20, 2012.
Dr Kohrt is an Assistant Professor of Oncology at the Stanford Cancer Institute. His research focuses on models of tumor
immunology, including vaccine therapy for patients undergoing bone marrow transplantation.
Dr Kaufman is Director of the Rush University Cancer Center, Associate Dean of the Rush Medical College, and Professor of Surgery and Immunology & Microbiology at the Rush University Medical Center. His primary research interests are in melanoma and tumor immunotherapy.
Dr Disis is Associate Member at the Fred Hutchinson Cancer Research Center, Professor in the Division of Medical Oncology, and Associate Dean of Translational Science at the University of Washington School of Medicine. She is involved in researching vaccines and immunotherapy for cancer.
Researchers presented the first large study to test the entire genome of individualized breast cancers to help personalize cancer at the 2012 ESMO Congress. They found that this approach is feasible and enables identification of genetic alterations that can be targeted by available drugs. They also saw early signs of [ Read More ]
Treatment with sorafenib did not improve overall survival (OS) in patients with heavily pretreated advanced non–small cell lung cancer (NSCLC) in the overall analysis of the MISSION trial reported at the 2012 ESMO Congress. A post hoc companion biomarker study of MISSION presented at the same meeting suggested that EGFR [ Read More ]