by Kimberly McGhee
Illustration by Emma Vought
Despite decades of a war on cancer, progress has been incremental, with new drugs offering patients only an extra few months of life. News that novel T cell–based immunotherapeutic approaches such as immune checkpoint blockade and adoptive cell transfer are achieving durable responses in patients with aggressive cancers has created excitement in the world of cancer research. It has raised hopes that the body’s immune system may be nimble, potent, and dynamic enough to eradicate tumors despite their ability to mutate and develop resistance, setting the stage for durable responses and cures. After years in the wings of cancer treatment, immunotherapeutics–previously used only as a last resort in patients who failed other therapies–is now taking center stage. Part I of this article will focus on immune checkpoint blockade and Part II, which will appear in the Fall 2015 issue of Progressnotes, on adoptive cell transfer.
Immune Checkpoint Inhibitors Uncloak Cancer
Immune checkpoint inhibitors are a novel class of immunotherapeutic agents that take the blinders off the immune system and enable T cells to “see” and target tumors that had previously been hiding in plain sight. In clinical trials of these new agents, durable responses and impressive gains in survival have been achieved, demonstrating that T cells are capable of mounting a successful defense against cancer–a point about which many had been skeptical until recently.
Much of that skepticism was erased when promising gains in survival were seen with ipilimumab (Bristol-Myers Squibb), an immune checkpoint inhibitor (specifically, a CTLA-4 inhibitor), in pretreated and untreated patients with advanced melanoma that had metastasized to the brain (NCT00094653 and NCT00324155, respectively).
According to MUSC Health hematologist/oncologist Keisuke Shirai, M.D., MSCR, who participated in an expanded-access trial of ipilimumab for advanced, metastatic melanoma before its approval by the FDA in 2011, ipilimumab is the “first agent [in] the last 30 years to provide survival benefit in stage 4 melanoma. The beauty of this drug is that, if patients respond, the response can be sustainable.” He is following up study patients three, four, and five years out who were once assumed to be terminal but who have now returned to work and lead relatively normal lives.
Of the pretreated patients receiving ipilimumab–patients who would otherwise only have had a few months to live–one fifth were alive at two-year follow-up,1 and twice as many patients who received ipilimumab in addition to standard of care (i.e., dacarbazine) were alive at five years compared with those given standard of care alone.2 A pooled analysis of data from ten prospective and two retrospective studies of ipilimumab, including two phase 3 trials, showed a median overall survival of 11.4 months, and a three-year survival rate of 22% in patients overall, 26% in untreated patients, and 20% in pretreated patients.3
Even more exciting is that immune checkpoint inhibitors are proving relevant not only to cancers that have historically shown some susceptibility to immunological approaches, such as melanoma and hematological cancers, but also to solid tumors. “With immune checkpoint inhibitors, we are harnessing the immune system to fight cancers that were previously thought to be resistant to immunotherapy,” explains Carolyn D. Britten, M.D., Director of the Phase 1 Clinical Trials Research Program at MUSC Hollings Cancer Center.
A number of recent high-profile articles have reported their efficacy in a broad range of tumor types. For instance, five letters published in the November 27, 2014 issue of Nature document “profound clinical response” in 175 efficacy-evaluable patients with a variety of cancers: confirmed objective response was observed in 18% of all study patients, 21% of patients with non-small cell lung cancer, 26% of patients with melanoma, 13% of those with renal cell carcinomas, and 13% of other tumors (e.g., colorectal cancer, gastric cancer, and head and neck squamous cell carcinoma).4 Preliminary data suggest that immune checkpoint blockade could be a promising approach for breast5 and ovarian6 cancer, and research is underway in a host of other cancers.
MUSC has had a long interest in T cell immunity. In the 1990s, surgeon and current MUSC President David J. Cole, M.D., opened one of the first immunology laboratories at MUSC focused on the role of T cells in tumor immunity. In the two decades since, a talented cadre of basic and translational immunologists, currently under the direction of Zihai Li, M.D., Ph.D., Chair of the Department of Microbiology and Immunology, has continued to work in close collaboration with hematologists/oncologists at MUSC Hollings Cancer Center to study the mechanisms underlying T cell immunity and further optimize T cell–based immunotherapies. Currently, trials of immune checkpoint inhibitors are underway at MUSC in patients with advanced melanoma, lung cancer, head and neck cancer, and glioblastoma. Phase 1 trials offer patients with many more types of cancers access to these exciting new immunotherapeutic agents.
How Immune Checkpoint Inhibitors Work
The job of the immune system is to distinguish between self and other and to mount a defense against invaders without harming the body’s own tissue. T cells are the body’s defenders, charged with eliminating threats from the outside. However, T cells in the vicinity of tumors may show little interest in cancer cells, which develop as a result of mutations to the body’s own cells and so are not perceived as a threat. Cancer cells often “hide” from neighboring T cells by hijacking a regulatory mechanism meant to prevent an attack on the body’s healthy cells (i.e., autoimmunity).
To prevent autoimmunity, the immune system has evolved a number of important safeguards. For example, the T cell, which is switched on when a receptor on the T cell surface binds to an antigen presented on the surface of antigen-presenting or tumor cells, can be switched back off when immune checkpoint proteins on T cells bind to their cognate proteins on tumors.
Immune checkpoint inhibitors block the binding of key immunosuppressive proteins such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1, a cognate protein for PD-1), enabling a robust T cell response.
In contrast to chemotherapeutic agents, which directly kill cancer cells at the expense of harming healthy cells, immune checkpoint inhibitors license the immune system to attack the malignancy. As a result, patients do not experience the side effects often associated with chemotherapy (e.g., nausea and vomiting, blood disorders, hair loss).
However, because these agents override a safeguard against autoimmunity, the T cells that have been licensed to attack cancer by immune checkpoint inhibitors could also target healthy tissues, causing inflammation. For example, patients receiving the CTLA-4 inhibitor ipilimumab may experience vitiligo (i.e., a loss of pigment or white patches in otherwise normally pigmented skin) and colitis, whereas those receiving anti-PD1 are more vulnerable to pneumonitis. These side effects are usually quite manageable with high-dose corticosteroid therapy and, in rare, intractable cases, with tumor necrosis factor (TNF)-blockers. However, these side effects can be life-threatening if they are not treated, and so physicians should be vigilant in monitoring for them as immune checkpoint inhibitors enter more broadly into the clinic.
Immune checkpoint blockade enables manipulation of a patient’s T cells, favoring effector T cells (that could promote a robust immune response against cancer) over regulatory T cells (that promote tolerance and help prevent autoimmunity). However, it may teach us how to more effectively approach autoimmune disease as well. In such diseases, it might be desirable to instead increase the number of regulatory T cells. A recent article by MUSC immunologist Shikhar Mehrotra, Ph.D., and colleagues reported a significant reversal of the depigmentation caused by vitiligo when the chemokine CCL22 was administered to mice to increase regulatory T cell numbers.7
Rapid Entry into the Clinic
Among those optimizing immune checkpoint therapy at MUSC are (from left to right) Dr. Shirai, Dr. Wu, and Dr. Lindhorst
Very recently, two PD-1 inhibitors received FDA approval–pembroluzimab (Merck) for ipilimumab-refractory advanced melanoma (September 2014) and nivolumab (Bristol-Myers Squibb) for medication-refractory unresectable or metastatic melanoma (December 2014). The latter approval came after impressive clinical trial results were reported for patients with untreated advanced BRAF wild-type melanoma: one-year overall survival was 72.9% in those treated with nivolumab vs 42.1% in those treated with standard-of-care dacarbazine.8
Melanoma was known to be amenable to immunotherapy, but few thought that this approach would be effective against other solid tumors, making the approval of nivolumab for the treatment of metastatic squamous non-small cell lung cancer (March 2015) an important milestone in the development of anticancer immunotherapy. Nivolumab’s approval for this indication also offered the benefit of this new class of immunotherapeutic agent to a much larger population of patients–about ten times as many people have lung cancer as have melanoma. Other immune checkpoint inhibitors are in the pipeline, including the PDL-1 inhibitors MPDL3280A (Roche/Genentech) and MEDI4736 (AstraZeneca).
“There are medications entering the clinic at a historically high rate–a remarkably high rate–that are really bending the curve in terms of survival,” explains MUSC hematologist/oncologist John M. Wrangle, M.D.
Researchers worldwide are making a concerted effort to bend that curve further. The most durable responses are seen only in a small cohort of patients, and so the search is on to identify biomarkers that could predict response. At MUSC, Shirai and Jennifer D. Wu, Ph.D., Associate Professor in the Department of Microbiology and Immunology, recently received Institutional Review Board approval to study biomarkers that could predict response and, once promising biomarkers have been identified, plan to open a trial to determine whether better responses are seen in patients identified as having those biomarkers.
Extending the Reach of Immune Checkpoint Therapy
Investigators at MUSC Hollings Cancer Center are developing novel concepts for clinical trials with these new immunotherapeutic agents in an effort to increase the number of patients with melanoma and lung cancer who achieve durable responses and to extend the benefits of immune checkpoint inhibitors to new populations of cancer patients.
Shirai and Wrangle are intent on bringing South Carolina’s large lung cancer population more clinical trials of next-generation immunotherapy. Shirai has already completed a trial randomizing patients with stage IV or recurrent PD-L1+ non-small cell lung cancer to nivolumab or the investigator’s choice of chemotherapy as first-line therapy (CheckMate 026, NCT02041533); data are under analysis by Bristol-Myers Squibb, the study’s sponsor. (Immune checkpoint inhibitors mediate better response in cancers with greater PD-L1 expression on their tumors.) That an immunotherapeutic agent is being assessed as a first-line therapy for lung cancer would have been unthinkable a decade ago and is testimony to immunotherapy’s entrance into the mainstream of cancer treatment.
Scott M. Lindhorst, M.D., who holds a dual appointment in the Division of Hematology/Oncology and the Department of Neurosurgery, is the principal investigator of a clinical trial evaluating the efficacy and safety of nivolumab vs the angiogenesis inhibitor bevacizumab, which is standard of care (CheckMate 143, NCT02017717), in patients with recurrent glioblastoma. Anecdotal accounts of prolonged survival after surgery in glioblastoma patients who develop an infection near the tumor bed suggest that immunotherapeutic approaches could play a role in treating this disease.
Other trials explore whether the potency of immune checkpoint inhibitors could be increased when administered with traditional anticancer treatments. The rationale behind combination regimens pairing a traditional therapy with an immune checkpoint inhibitor or other novel immunotherapeutic agent is that lower-dose chemotherapy may kill enough tumor cells to “prime” the immune system by freeing more antigen for T cell presentation. Surgery could also elicit a robust T cell response. Immune checkpoint inhibitors would prevent the activated T cells from being turned back off. Shirai is in the process of opening a trial at MUSC that will explore whether ipilimumab or nivolumab is more effective at preventing recurrence after complete resection of Stage IIIb or Stage IV melanoma (CheckMate 238, NCT02388906).
Regimens combining more than one immune checkpoint inhibitor are also being studied to determine whether the impressive results seen with such combination therapies in melanoma can be replicated in other cancers. The combination of a CTLA-4 inhibitor and a PD-1 inhibitor looks especially promising. A recent phase 1 dose-escalation study of patients with melanoma and a known BRAF mutation (NCT01927419) showed that 22% of patients receiving combination therapy with ipilimumab (a CTLA-4 inhibitor) plus nivolumab (a PD-1 inhibitor) but none of those receiving ipilimumab alone achieved a complete response.9 A phase 2 trial at MUSC Hollings Cancer Center led by Shirai is testing the efficacy of the PD-L1 inhibitor MEDI4736, the CTLA-4 inhibitor tremelimumab (Pfizer), and a combination of the two in patients with PD-L1– squamous cell carcinoma of the head and neck (NCT02319044). By late 2015, Shirai and Wrangle plan to open a trial of a combination regimen of nivolumab and ipilimumab in lung cancer.
Under Britten’s leadership, MUSC Hollings Cancer Center has recently opened and is recruiting patients for two phase 1 trials of PD-L1 inhibitors. Some speculate that PD-L1 inhibitors may be associated with fewer autoimmune side effects because they block the binding of PD-1 and PDL-1, known to be immunosuppressive, but do not interfere with the binding of PD-1 to PD-L2.
One trial is an open-label dose-escalation trial of the PD-L1 inhibitor avelumab (MSB0010718C; EMD Serono/Merck) with consecutive parallel group expansion in patients with metastatic and locally advanced solid tumors (NCT01772004). Now that the safe and tolerated dose has been determined, avelumab is being administered to patients with diverse tumor types, including non-small cell lung cancer, head and neck cancer, and urothelial cancer. The design of this trial will enable patients in South Carolina with a wide variety of cancers to have access to an exciting new class of anticancer agents.
The second phase 1 trial (NCT02118337) is an open-label study intended to evaluate the safety and tolerability of a combination regimen of the PD-1 inhibitor MEDI0680 (MedImmune/AstraZeneca) and the PD-L1 inhibitor MEDI4736 (MedImmune/AstraZeneca) in patients with advanced malignancies. The PD-1 inhibitor prevents the binding of PD-1 to PD-L1 but does not prevent PD-L1 from binding to other proteins. The rationale for a combined PD-1/PD-L1 regimen is that the PD-1 inhibitor would block PD-1/PD-L1 binding and the PD-L1 inhibitor would prevent all other PD-L1 binding. MUSC Hollings Cancer Center is one of only a handful of cancer centers in the country offering this novel combination of therapies in a phase 1 trial.
Immunologists at MUSC are focused on working with their clinical colleagues to improve immune checkpoint blockade. Mark P. Rubinstein, Ph.D., is studying the mechanism by which immune checkpoint inhibitors revive T cell function in the tumor. Chrystal Paulos, Ph.D., has partnered with Shirai to study the immunological mechanisms underlying the effectiveness of CLTA-4 and PD-1 therapies in patients with melanoma and lung cancer. Wu, who has developed a unique humanized bi-transgenic mouse model of prostate cancer,10 was awarded a Department of Defense grant this year to use the mouse model to study how CTLA-4 therapy could be enhanced for patients with prostate cancer. Wu plans to use her unique mouse model to explore how PD-1 checkpoint therapy could be improved across a variety of cancer types. Li has just received a five-year grant from the National Cancer Institute to further improve T cell checkpoint inhibitors by combining the strategy with inhibitors of thrombocytes or platelets.
The arrival of immune checkpoint inhibitors in the clinic—and the growing number of cancers in which they are showing promising signs of efficacy–has ushered in a new era of cancer treatment. Once a casualty of more traditional approaches such as chemotherapy and radiation, the immune system is now assuming a leading role in the fight against cancer.
Part II of this article will appear in the Fall issue of Progressnotes and will explore other immunotherapeutic approaches with strong clinical promise, including adoptive cell transfer, and how they could potentially be combined with immune checkpoint blockade to achieve even better responses.
For more information on enrolling a patient in one of the immune checkpoint inhibitor trials, contact the main MUSC clinical trials office at 843-792-9321.
1 McDermott D, et al, for the MDX010-20 investigators. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Annals of Oncology 2013;24:2694-2698.
3 Schadendorf D, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. Journal of Clinical Oncology. Published ahead of print on February 9, 2015. Available at http://dx.doi.org/10.1200/JCO.2014.56.2736
4 Romano E, Romero P. The therapeutic promise of disrupting the PD-1/PD-L1 immune checkpoint in cancer: unleashing the CD8 T cell mediated anti-tumor activity results in significant, unprecedented clinical efficacy in various solid tumors. Journal for Immunotherapy of Cancer (2015) 3:15.
5 Ravelli A, et al; for the Solid Tumor Working Party of the European Blood and Marrow Transplantation Society. Immune-related strategies driving immunotherapy in breast cancer treatment: a real clinical opportunity. Expert Rev Anticancer Ther. 2015 Apr 30:1-14.
6 Wang DH, et al. Checkpoint inhibitors in immunotherapy of ovarian cancer. Tumour Biol. 2015 Jan;36(1):33-39.
7 Eby JM, Kang H-K, Tully ST, Bindeman WE, Peifferi DS, Chatterjee S, Mehrotra S, Le Poole C. CCL22 to activate Treg migration and suppress depigmentation in vitiligo. J Invest Dermatol. 2015 E pub ahead of print 12 March 2015. Available at http://dx.doi.org/10.1038/jid.2015.26.
8 Robert C, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372:320-30.
9 Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015. Published online first on April 20, 2015. Available at http://dx.doi.org/10.1056/NEJMoa1414428
10 Liu G, Lu S, Wang X, Page ST, Higano CS, Plymate SR, Greenberg NM, Sun S, Li Z, Wu JD. Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis. J Clin Invest. 2013 Oct;123(10):4410-4422.