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CICON16: The Power of Combinations

September 30, 2016

On Day 3 of CICON16, the name of the game was combinations. Single treatments work against some cancers, especially if they’re caught early, but they’re often ineffective against advanced tumors. Moving forward, experts in the field believe that combination treatments will be crucial to addressing cancer’s complexity and enhancing the immune system’s anti-tumor activity to benefit more patients.

Ira MellmanDeciding which treatments to combine is no easy task though. Traditionally, as Genentech’s Ira Mellman, Ph.D., a member of CRI’s Scientific Advisory Council, reminded the audience, this has been done by “mixing and matching” different agents without much understanding of their potential synergy and then hoping for the best. However, with so many different drugs available now, we need a smarter and more efficient way to choose the combinations that are most likely to work. That starts with identifying the survival strategies that cancer exploits and then pairing treatments to stop them. Day 3 showcased some of the promising new strategies that were guided by this approach.

Mellman, a member of both CRI’s Cancer Immunotherapy Consortium (CIC) and Scientific Advisory Council (SAC), first discussed the combination of anti-PD-1 nivolumab and anti-CTLA-4 ipilimumab. Both of these checkpoint immunotherapies “release the brakes” on the immune response, but they release different brakes. As a result, combining them has non-redundant activity, and has proven more effective against melanoma than either alone. Unfortunately, this combination is associated with significant toxicity, and approximately 30% of patients have to stop the treatment early, although an association between these treatment-related adverse events and clinical benefit has been found in other studies treating patients with this combination.

He also discussed other combinations that involve anti-PD-L1 (atezolizumab) therapy. The first uses oxaliplatin, a chemotherapy drug that leads to increased cancer cell antigen presentation, dendritic cell maturation, and anti-cancer T cell activity. The second uses an inhibitor of the MEK pathway, which cancer cells use for growth. MEK inhibition improves survival of anti-cancer T cells and also increases antigen presentation on cancer cells. Each of these two drugs synergized with anti-PD-L1 immunotherapy has led to enhanced anti-cancer activity by utilizing distinct anti-tumor mechanisms. This was especially important for patients with colorectal cancer, who are usually resistant to either anti-PD-1 or MEK inhibition individually, but who responded to them in combination. Combining an anti-PD-L1 treatment with an antibody that blocks TIGIT, which reduces the effectiveness of a type of immune cell called a natural killer cell, was also effective against colorectal cancer in mice. This strategy is now being tested in a phase 1b clinical trial, along with another strategy that combines anti-PD-L1 treatment with an antibody that activates OX40, a kind of “go” signal that boosts the anti-cancer activity of killer and helper T cells.

Next up was Drew Pardoll, M.D., Ph.D., who, in addition to serving as the director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at the Johns Hopkins University School of Medicine, is also co-leader of the SU2C-CRI Dream Team as well as a member of CRI’s SAC and Grant Review Committee. Immunotherapy has most often been used as a last resort after surgery, chemotherapy, and radiotherapy have failed; however, in a clinical trial that Pardoll is leading as part of his Dream Team work, he showed that lung cancer patients can benefit from anti-PD-1 nivolumab even when it’s given before surgery. Almost half of these patients had major responses (more than 90% of tumor disappeared), and all of their tumors that were removed had significant infiltration of anti-cancer T cells. The logic behind these responses (which the data support) goes as follows: first, nivolumab expanded the anti-cancer T cell populations in the tumor, and second, surgery caused them to spill out into circulation where they could target distant metastatic tumors. Already, this promising early data encouraged and enabled Pardoll’s team to plan ahead for a phase 3 trial testing nivolumab’s pre-surgical effectiveness.

David ReardonDavid Reardon, M.D., an oncologist at the Dana-Farber Cancer Institute, next focused on another use for PD-1 pathway blockade in combination with a targeted treatment. In a clinical trial funded by CRI through our Clinical Accelerator, Dr. Reardon is treating glioblastoma (GBM) patients with the combination of the anti-VEGF antibody bevacizumab, which blocks blood vessel formation, and durvalumab, which targets the PD-L1 molecules that are expressed in 80% of GBM patients. This was able to cure some mice with GBM and induced immune memory that prevented relapse, and will hopefully prove effective in human GBM patients being treated with the combination as well.

The next speaker, Martin Oft, M.D., founder and vice president of ARMO BioSciences, showcased the use of a new treatment named AM0010, which is a modified, longer-lasting version of IL-10. IL-10 is normally regarded as anti-inflammatory, but it has also been found to stimulate the proliferation and anti-cancer activity of T cells, prompting its use in combination with anti-PD-1 pembrolizumab in a phase I clinical trial. Some patients from this trial have had durable responses of over a year, and tumor responses were found to correlate with expansion of anti-tumor T cells. Additionally, an increase in T cells that expressed the inhibitory LAG-3 and PD-1 receptors actually coincided with tumor shrinkage.

Another interesting approach was then presented by Christina Coughlin, M.D., Ph.D., the chief medical officer of ImmunoCore. IMCgp100 is a molecule with dual functionality that binds both to the melanoma antigen gp100 and the T cell receptor. In this way, it can connect T cells with melanoma cells and encourage them to attack when they otherwise wouldn’t. In the first human trial, some complete responses were achieved in patients with one type of melanoma. Now, IMCgp100 will be combined with either anti-PD-L1 durvalumab, anti-CTLA-4 ipilimumab, or both together.

While anti-PD-1/PD-L1 and anti-CTLA-4 drugs prevent T cells from becoming “exhausted” and ineffective, another way to enhance their anti-cancer activity is to target a receptor known as ICOS (inducible T cell co-stimulator) that enhances their proliferation, survival, and memory, sometimes even in the face of inhibitory factors. Patrick Mayes, Ph.D., the director of Biology for the Immuno-Oncology and Combinations Discovery Performance Unit at GlaxoSmithKline, discussed their success with this approach. ICOS+ T cells exist in many different types of tumors, and were able to exert anti-cancer activity in mice that were treated with the ICOS-activating antibody H2L5. Furthermore, when combined with anti-PD-1 therapy, this therapy enabled complete and durable cures in 80-100% of mice with colorectal cancer, which is usually resistant to anti-PD-1 therapy alone. When this combination was used on human tumor samples, it also showed promising behavior, including enhancement of interferon signaling in both tumor and blood-based T cells.

Next, Juan C. Jaen, Ph.D., president of Arcus Biosciences, discussed a combination treatment that targets the high levels of adenosine found in many tumors. By itself, the anti-CD73 inhibitor A000830 was able to reverse adenosine-associated inhibition of anti-cancer T cells, and improve their growth and survival. And when it was combined in mice with anti-PD-1 therapy, it increased the infiltration of T cells into colorectal cancer tumors and improved the ratio of anti-cancer T cells to pro-cancer immune cells.

With the recent approval of the oncolytic virus therapy Talimogene laherparepvec (T-Vec) against melanoma, it too is being investigated for use in combination treatments. David Reese, M.D., Amgen’s senior vice president of translational sciences and a member of CRI’s Cancer Immunotherapy Consortium Steering Committee, discussed efforts using this modified herpes virus that has been engineered to kill cancer cells and activate an immune response through the release of tumor antigens and the immune-stimulating GM-CSF.

Finally, K. Dane Wittrup, Ph.D., associate director of the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, wrapped up Day 3 with his efforts to enhance immunotherapy’s effectiveness by driving an innate immune response that strengthens the adaptive immune response against cancer. His strategy uses a molecule called knottin to target integrins, the molecules that allow cancer cells to physically interact with their surroundings and are important for their invasion, proliferation, and survival. However, knottin by itself isn’t very useful, so through sophisticated molecular engineering Wittrup converted it into a “pseudo-antibody” that binds integrins on one end and innate immune cells on the other. This exposes the innate immune system to cancer and kickstarts its anti-tumor activity, which includes providing the adaptive immune system with ways to identify cancer. Wittrup also created a modified version of the pro-immune IL-2 molecule that increases the duration of its activity. When he combined his anti-tumor pseudo-antibody and this modified IL-2 with an adaptive immune-enhancing anti-PD-1 therapy, he was able to produce durable cures in almost all of the mice he treated, including those with large, established tumors.

These were just some of the promising combination therapies presented this year at CICON16, and although many of them are still early on in their clinical / pre-clinical development, there are great reasons to believe that at least some of these will be available to benefit human patients sooner rather than later.

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