Hot Topics in Immunotherapy and Targeted Therapy

This blog post is an excerpt from a Q&A posted on the Cancer Research Catalyst blog, the official blog of the American Association for Cancer Research. The interview was done with Dana-Farber’s Levi Garraway, MD, PhD, in advance of the International Conference on Molecular Targets and Cancer Therapeutics.


What is the scope for personalizing immunotherapy?

Some would say that immunotherapy is the most targeted therapy of all, because the way the immune system recognizes and attacks a tumor is arguably more “personalized” than molecularly targeted therapies.

cancer research, Levi Garraway
Levi Garraway, MD, PhD, is a Dana-Farber researcher who focuses on cancer genomics, personalized medicine, and targeted therapies.

At this point, unlike targeted therapy, we are not quite as far along in predicting who will respond and who will not respond to the different types of immunotherapies. There are some biological features that are emerging, and we expect to hear to some interesting updates on the molecular basis of response. Obviously, if we could elicit greater insights into the molecular characteristics of responders and non-responders, we would be in a much better position to stratify patients, particularly for the immunotherapy combination regimens that are now emerging. We recently had the first immunotherapy combination approved by the FDA to treat melanoma, but the combination is often much more toxic than single agents. An immune checkpoint inhibitor (accompanied by a diagnostic test for PD-L1 expression) was also approved by the FDA recently for squamous lung cancer patients. Having a molecular basis to predict response and enrich for those patients most likely to respond across tumor types will be an important next step with immunotherapies.



What is the latest in combining targeted therapies with immunotherapies?

It is becoming very clear that durable control of cancer is going to require combinations, either of targeted therapy or immunotherapy or both. So this is something that’s of great interest. There are several studies ongoing that are testing such combinations. For example, some teams are combining RAF and MEK inhibitors with immune checkpoint inhibitors, particularly anti-PD1 therapies, such as pembrolizumab. Some oncologists are effectively trying such approaches “off-label,” since both targeted therapies and immunotherapies are FDA-approved for melanoma. One hypothesis is that giving targeted therapy first followed by immunotherapy could potentially release the antigens masked by the tumor cells that the immune system can recognize.

Another concept is to use targeted therapy to shrink the tumor and then treat it with immunotherapy to increase the durability of the responses; however, this idea is still at a relatively early stage of clinical evaluation. We will definitely be hearing from scientists who have either been doing preclinical studies along these lines or have been testing them in early clinical trials, and hopefully we will get a flavor of what the outlook is for these approaches.



What are the potential areas to watch for, moving forward?

We are going to see early clinical data emerging from a whole variety of new immunotherapy drugs in the future. There are antibodies targeting other immune checkpoint-related molecules besides CTLA-4 and PD1/PD-L1, such as LAG3, TIM3, and TIGIT, which are of interest therapeutically. Then there are STING agonists, which may draw immune cells into the tumor. And then there are other small molecules that inhibit different types of proteins that regulate immune responses, such as IDO.

So, I would say, looking forward, I would expect to see a significant proliferation of data emerging on immunotherapy drugs that might come out of next year’s Molecular Targets meeting or even as early as the AACR Annual Meeting 2016.

There are major tumor types in which we have not been able to make the kind of inroads with immunotherapy that we would’ve liked. Microsatellite-stable colorectal cancers and prostate cancer, for example, seem to be largely refractory to the immunotherapies that are currently available to us. In breast cancer, there are hints that some triple-negative tumors may be responsive to immunotherapy. But the ER/PR-positive and HER2-positive breast cancers, which constitute the vast majority of breast cancers, do not seem to be especially responsive to immunotherapies, particularly when in advanced stages.

So there’s clearly a lot of work to do in figuring out how to turn the nonresponsive tumor types, which are still the lion’s share of cancer burden, into tumors that are responsive to immunotherapies and/or combinations.

Furthermore, there is a lot more work to do to understand intrinsic and acquired resistance to immunotherapies. Some patients who respond to immunotherapy initially have disease progression eventually. We will be hearing more about them going forward. And, hopefully, learning about the underlying tumor biology will teach us how to keep recurrences at bay once a response has been achieved.

Clearly, there is a lot of excitement in the field. And yet, there is so much more to do.