Immune Checkpoint Inhibitors: What’s Next?

Yervoy® (ipilimumab), which targets the CTLA-4 checkpoint molecule on activated immune cells, has been at the vanguard of checkpoint inhibitors, and was approved to treat melanoma in 2011. Patients with melanoma got more good news in 2014, with the FDA approval of Merck’s Keytruda® (pembrolizumab) and Bristol-Myers Squibb’s Opdivo® (nivolumab), which target the PD-1 pathway. Several ongoing studies suggest PD-1 pathway inhibitors may benefit patients with a number of cancers, including lung, brain, head and neck, kidney, and other cancers.

Immunotherapies targeting CTLA-4 and PD-1 have gotten quite a lot of press recently. And for good reason: they are radically improving the treatment odds of many patients with cancer. But these two checkpoints are really just the beginning. There are many other checkpoint inhibitors in the drug development pipeline, and the Cancer Research Institute is leading the charge to bring them to patients.

On the Flip Side: PD-L1 Inhibitors

PD-L1, which is expressed on cancer cells and makes the immune response shut down, has been seeing positive results. One PD-L1 inhibitor is called MPDL3280A, which is being developed by Roche/Genentech and received “Breakthrough Therapy” designation from the FDA for bladder cancer in June 2014. It is in phase III testing for bladder cancer and non-small cell lung cancer, and is in phase I and II trials for melanoma, kidney cancer, lymphoma, and solid tumors. Bryan A. Irving, a 1996-1999 CRI postdoctoral fellow who joined Genentech in 2001, led studies that culminated in the generation of MPDL3280A.

Another PD-L1 antibody is called MEDI4736, and is being developed by AstraZeneca/MedImmune. Through its Clinical Accelerator program, CRI sparked an innovative deal with its developer to bring MEDI4736 to patients. It is part of the growing repertoire of promising immunotherapies available for testing in our global cancer immunotherapy clinical trials network. MEDI4737 is in clinical trials for a number of cancers, including brain, cervical, colorectal, head and neck, kidney, lung, and ovarian cancers.

Costimulatory/Coinhibitory Molecules

The quality of the immune response of T cells is controlled by costimulatory and coinhibitory signals. CTLA-4 and PD-1/PD-L1 are coinhibitory signals that put the brakes on the immune response. Costimulatory molecules, on the other hand, are designed to enhance pre-existing anti-cancer immune responses. Through its Clinical Accelerator program, CRI has access to TRX518, an anti-GITR antibody, being developed by GITR, Inc. TRX518 is designed to enhance the immune response by enabling T cells to be more effective in attacking cancer cells. It is in a phase I trial that is enrolling patients with melanoma or other solid tumors at Memorial Sloan Kettering Cancer Center, University Hospitals in Cleveland, and the Cleveland Clinic (NCT01239134). TRX518 is the first treatment of its kind ever to be tested in human cancer patients. Another GITR antibody is MK-4166, which is produced by Merck. It is in a phase I trial for solid tumors, which started in June 2014.

4-1BB, also known as CD137, is a costimulator for activated T cells. By serving as an agonist—a chemical that binds to a receptor and activates it to produce a biological response—the anti-4-1BB antibody stimulates the first wave of the anti-tumor reaction. Lieping Chen (1999-2001 CRI preclinical grant) was funded by CRI to generate an antibody against 4-1BB. He is a holder on numerous patents related to 4-1BB and its binding agents. There are two 4-1BB antibodies in development for a number of cancers: urelumab (BMS-663513), being developed by Bristol-Myers Squibb, and PF-05082566 (PF-2566), being developed by Pfizer.

---

[Related] Listen in to NPR’s interview with Dr. Julie Brahmer about checkpoint inhibitors

---

Kunle Odunsi (Scientific Advisory Council member and grantee) and colleagues have demonstrated that two inhibitory molecules, PD-1 and LAG-3 (lymphocyte activation gene 3), collaborate in suppressing the anti-tumor T cell immune response. Moreover, by giving a combination of antibodies that block PD-1 and LAG-3, they could restore T cells to full function resulting in stronger anti-tumor immunity. In a phase I trial by Bristol-Myers Squibb, a LAG-3 antibody (BMS-986016) and Opdivo (nivolumab) are being tested in patients with solid cancers. They are enrolling at the University of Chicago under Thomas Gajewski (1998-2002 investigator award and CRI Scientific Advisory Council member), Johns Hopkins University under Charles Drake (predoctoral sponsor and SAC member), Dana-Farber Cancer Institute under F. Stephen Hodi (clinical trials network member), and Memorial Sloan Kettering Cancer Center under Margaret Callahan (2012-2014 CRI postdoctoral fellow) (NCT01968109).

Timothy N.J. Bullock (2005-2010 CRI investigator award), at the University of Virginia Health System, showed that a monoclonal antibody designed to activate the CD27 costimulatory molecule—which plays an important role in the activation, survival, and differentiation of T cells—caused substantial reduction in the progression of lung metastases and primary tumors in a model of melanoma. An agonist anti-CD27 antibody is being developed by Celldex, under the name varlilumab (CDX-1127). It is being tested in a phase I trial for CD27-expressing B cell cancers, any T cell cancer, and solid tumors, including melanoma, kidney cancer, prostate cancer, ovarian cancer, colorectal cancer, and lung cancer. It is also being tested with the vaccine ONT-10, which targets the MUC1 antigen, in breast and ovarian cancers.

CD40 was originally discovered by Edward A. Clark (1978-1980 postdoctoral fellow) and Jeffrey Ledbetter, as an activating protein on the surface of B cells[i]. The CD40 pathway is now understood to activate dendritic cells and license them to promote CD8+ T cell activation and proliferation. A number of clinical trials testing CD40 agonists as an immunotherapy for cancer are complete. One being studied is CP-870,893, being developed by Pfizer. In a phase I clinical trial, Gregory L. Beatty (2013-2017 CRI grantee, pictured left) and Robert H. Vonderheide (Scientific Advisory Council member) treated 21 patients with pancreatic cancer, and got a partial response in five. A phase II study is being planned.

There are many more checkpoint inhibitors/immune modulators in the pipeline—OX40, TIM-3, ICOS, BTLA, and more. Their combination will soon transform the treatment of many if not all types of cancer. Give today to help CRI continue to fund breakthrough research that is revolutionizing cancer treatment.

[i] Clark EA, Ledbetter JA. Activation of human B cells mediated through two distinct cell surface differentiation antigens, Bp35 and Bp50. Proc Natl Acad Sci USA 1986; 83: 4494–8. (PMID: 3487090)