AACR 2019: Treating Cancer in the Age of Precision Medicine
Combination therapies, deciphering the tumor microenvironment, studying rare cancers and AI are important tools in fighting cancer more precisely
Last year alone, an estimated 1.7 million new cases of cancer were diagnosed in the United States, according to the National Cancer Institute. That amounts to around 4,750 cases every day. And according to the International Agency for Research on Cancer, the number of new cancer cases per year worldwide is expected to rise to 23.6 million by 2030, nearly a two-thirds increase from 2012.
Fortunately, the arsenal we use to combat cancer is larger, more sophisticated and increasingly more effective in attacking some of the deadliest cancers, including melanoma, gastric and lung cancers. Leading the pack are cancer immunotherapies, which appeared in clinics nearly a decade ago and have, without a doubt, revolutionized the field of oncology. Over the past few years we have seen unprecedented clinical responses, rapid drug development, and first-in-kind approvals from the U.S. Food and Drug Administration.
However, the currently approved immuno-oncology drugs have not turned out to be the magic bullet to cure or tame all cancers. The painful reality is that cancer immunotherapies successfully treat only a minority of patients. We still do not fully understand why some patients respond better to the drugs than others, or why other patients have no response at all. Which begs the question, what is the next chapter in cancer research? Will immune checkpoint inhibitors continue to dominate or will other strategies take the lead? These are important but difficult questions to answer as the American Association for Cancer Research (AACR) Annual Meeting gets underway in Atlanta, Georgia, this weekend.
As a contract research organization whose partners span the gamut from academic labs and startups to large pharma companies and biotechs with global reach, our vantage point allows us to see a future increasingly determined by precise tools and therapies aimed at precise patient populations. In other words, 21st century cancer R&D will be less about the broad spectrum and more about customization, with a lot of hit and miss in between. Immunotherapy and the strategies aimed at enhancing anti-tumor immune responses provide excellent examples of this perspective.
Recent efforts to increase the number, depth and duration of responses to immunotherapy have centered on combination strategies. For example, will treatment with 2 immune checkpoint inhibitors be more effective than treatment with just one agent? The answer, so far, is that it depends! The efficacy of combination therapies is very much related to the antibody target and tumor type. For example, a combination of 2 FDA-approved immune cell checkpoint inhibitors is more effective than either alone in patients with advanced melanoma. Conversely a combination of one of these immune checkpoint inhibitors with another experimental immunotherapy failed to meet primary efficacy endpoints in a large phase 3 clinical trial in the same tumor type. While this and the failure of other combination strategies have cast doubts and decreased excitement on the potential of combination immunotherapies as near-term treatment options, there are other ongoing studies aimed at matching an immunotherapy with a targeted therapy or that combine immunotherapy with chemotherapy that look more promising.
One such example is the partnering of a PARP inhibitors with an immune checkpoint inhibitor to treat women with BRCA-related ovarian and breast cancers. Early stage clinical studies found that pairing a PARP inhibitor with an immunotherapy anti-PD1 checkpoint inhibitor increased tumor shrinkage in 25% of patients with ovarian cancer. At the preclinical level, the crosstalk that our researchers observed between PARP inhibitors and immune checkpoint inhibitors in different breast cancer mouse models suggest this drug combination might be effective in women with triple-negative and / or BRCA-1 mutated breast cancers.
Immunotherapy and the Tumor Microenvironment
One way we might be able to make cancer treatments more precise and more effective is by learning more about tissues in and around the tumor, the so-called tumor microenvironment. The tumor cells, associated stroma, endothelial cells, extracellular matrix, immune cells, cytokines and chemokines cooperate to support an immunosuppressive environment. Scientists have likened the tumor microenvironment to a garden where the small number of weeds that escape being yanked, eventually overtake the landscape and ruin the potential of a perfectly good harvest. Targeting the different components of the TME that promote tumor growth and metastasis through anti-tumor immune suppression is therefore similar to finding the right weed killer—there are lots of options but no clear one-size-fits-all product . We have already amassed an arsenal of weapons to fight tumor cells, vasculature, and suppressed T cells using chemotherapeutics, targeted biologics, small molecules and immune checkpoint inhibitors; but a lot more work is needed to work out how, when and in whom to use this arsenal. Our scientists and partners are working diligently to develop the necessary in vitro and in vivo tools needed to model the tumor microenvironment and uncover innovative solutions for precision medicine.
Rare cancers such as sarcomas offer one of the clearest reasons why precision medicine matters. There are few if any approved treatments for these tumors. The rarity of these cancers together with their often dismal survival rates means that clinical trials and collection of adequate clinical specimens are difficult. Nevertheless it is possible to use next-generation sequencing and other high content tools to identify potentially targetable genomic alterations in small tissue samples, and then assess their clinical utility in drug development.
Artificial intelligence (AI) is also being used increasingly to identify novel cancer drugs or drug targets, such as predicting tumor progression from tumor DNA in blood samples, analyzing genomic data related to cancer and identifying suitable targets for vaccines and antibodies from complex immunological data. This tool will be key in moving us closer toward finding customized solutions for cancer patients.
So what will be the next chapter? We are making enormous strides in using next-generation tools to attack cancer, but in order to imagine a world where we can treat every person’s cancer effectively we will need more collaboration and innovation. And we shouldn’t ever assume that one class of drugs will be the answer.