the Janssen Pharmaceutical Companies of Johnson & Johnson
The Cancer Immunotherapy Treatment Paradigm
Charles G. Drake
Please comment on your current role and responsibility in leading the cancer immunotherapy research and development at Janssen?
I lead the immuno-oncology team at Janssen where our efforts are focused on the discovery and development of next-generation approaches to immunotherapy that include antibody-based drugs, cell therapies, and novel cancer vaccines.
One especially promising approach that we are working on is allogeneic cell therapy, derived from induced pluripotent stem cells (IPSC). The objective is to convert these IPSC into immune cells that can fight cancer by engineering them ex vivo. This is incredibly significant as these stem cells can grow perpetually in culture, becoming a potentially inexhaustible source for treating cancer in a wider array of patients.
What are some of the challenges you have witnessed in the cancer immunotherapy space, and how do you align yourselves accordingly?
There are a number of challenges involved in bringing cancer immunotherapy to the patients that could benefit. One major difficulty is translating laboratory data into clinical data, i.e. predicting which agents will work in patients as our current models are reasonable, but far from perfect.
Take for instance lymphocyte activation gene3 (LAG-3), which was discovered as an immune checkpoint in 2004, showing that it was synergistic with anti-PD-1 in terms of anti-tumor effects. Those studies were performed in animal models in the first line setting. But when this drug was taken to the clinic, it was tested after initial therapies, i.e. mostly in the second and third line settings. So, its activity was not impressive. Finally, after many years, the clinical studies were aligned with the initial murine studies, i.e. the anti-LAG-3 / antiPD-1 combination was tested in the first line in patients with melanoma. Those data were impressive, the combination doubled progression-free survival, leading to approval.
On the other hand, there have been a fairly large number of trials in which promising laboratory results just did not pan out as expected. Take for example T cell immunoglobulin and ITIM domain, or TIGIT, where laboratory studies targeting TIGIT were quite impressive. Beyond that, a reasonably-sized randomized clinical trial in patients with lung cancer showed that anti-TIGIT combined with anti-PD-L1 may help treat lung cancer. Nevertheless, the larger, confirmatory (Phase III) trial was negative, for reasons that are really not clear.
We are advancing combinations that we believe will be effective in activating the immune system in a way that leads to long-term remissions for patients with cancer.
There are also some interesting examples showing mixed results. One of these involves a class of drugs designed to localize T cells to tumors and to activate them in the process. These go by many names, including bi-specifics, BITE’s or T cell redirectors. They’re fascinating molecules, marvels of modern genetic and protein engineering in which one arm of an antibody targets a tumor antigen, and the second is directed against T cells via CD3. In hematological malignancies like lymphoma and multiple myeloma, these molecules have been quite successful, with the majority of treated patients showing significant tumor shrinkage. But in common solid tumors like prostate cancer, results have been decidedly mixed as there these drugs are not quite ready for prime time. We do have some good ideas on how to increase activity, since T cells need two signals for full activation and we’re working hard to generate drugs that will provide that second signal, which may be critical.
Would you like to share about your current cancer immunotherapy project?
One super-exciting area of interest involves cancer vaccines, which have a checkered history to say the least. Most of the prior studies focused on shared tumor targets, i.e. antigens that are expressed in both normal tissue and in cancer. Instead, we’re leveraging advanced computational algorithms to discover targets expressed only in the tumor; these targets are the products of disordered RNA splicing in many cancers and are known as “dark matter”. In addition to targeting novel antigens, we’re also planning to use a state-of-the-art vaccine strategy, involving two different vaccine types for a prime and a boost, in combination with an immune checkpoint blocker. Definitely an innovative approach!
How do you envision the future of cancer immunotherapy?
Well, the future is hard to predict. About 10 years ago most of us would have predicted that combining immune checkpoint blockade (like anti-PD-1) with other agents would be a home run. Clearly that’s not been the case. Currently, cell therapies continue to take center stage for hematological cancers, but it’s not clear if that can translate to common solid tumors like prostate cancer and breast cancer. While we’re working hard on that, it’s important to keep in mind that Rome wasn’t built in a day, that is it will likely take a number of iterations in the clinic before we get it right. But we recognize that patients are waiting, so we’re a team that never settles in recognizing this massive unmet need.
What would be your single piece of advice to an aspiring professional in your field?
Sometimes I find scientists coming into the industry are looking at animal data becoming deeply impressed and believing wholeheartedly that those results will translate precisely in clinical trials. That’s just not the case. Our collective experience is that many drugs/combinations work really well in animal models but only moderately so in humans. Sure, well-done studies in mice can teach us a lot about mechanism and combinations, but it's a mistake to make the leap that things will be the same in patients. The goal, then, should be got get those promising combinations and agents into patients as soon as we can; that’s the only way we’re going to eliminate cancer in our lifetime.
