Over the past few years, cancer immunotherapy has made substantial progress and become an important treatment option for patients with a variety of cancers. However, despite the fact that three years in a row now an immunotherapy-related breakthrough has been named the Advance of the Year by the American Society of Clinical Oncology, one could perhaps be forgiven for not realizing how much of an impact it’s already made in the clinic.
That all changed at the 2018 annual meeting of the American Association for Cancer Research, where immunotherapy dominated the headlines.
After Day 1’s introductory and educational sessions—many of which also focused on immunotherapy—Day 2’s opening plenary session kicked off with talks about potential next generation checkpoint immunotherapies, a dendritic cell-based vaccine that was able to enhance existing immunity as well as generate new responses in patients with ovarian cancer, and a promising personalized neoantigen vaccine that is being evaluated in multiple phase I clinical trials.
Day 3 was when immunotherapy shone the brightest. Even before the sessions started, the FDA announced the approval of a checkpoint immunotherapy combination for first-line treatment of advanced kidney cancer. Then, beginning with the morning press briefing, results from three phase III clinical trials revealed the benefits of combinations involving PD-1 checkpoint immunotherapy as first-line options for patients with advanced lung cancer, while a pilot study showed that lung cancer patients who received the PD-1 immunotherapy prior to surgery experienced significant protection against relapse, at least compared to historical rates.
Beyond the impressive clinical breakthroughs, Day 3 also highlighted how checkpoint immunotherapies affect immune cell memory, how CD40-targeting immunotherapies and radiation complement checkpoint immunotherapy through independent mechanisms, and how targeting metabolic factors in the tumor microenvironment might be able to improve immune responses against tumors.
Nearly overshadowed by the lung cancer news in that morning’s press briefing was a breakthrough that involved the creation of ready-made, “universal” CAR T cells derived from stem cells, which could conceivably be given safely to any patient without manufacturing downtime seen with current, personalized CAR T therapies.
Day 4 presented results from several encouraging combination trials in which the effectiveness of PD-1 checkpoint immunotherapy was enhanced through strategies that blocked immunosuppressive pathways, such as TGF-b, as well as those that engaged the innate immune system by activating Toll-like receptor (TLR) pathways. Dendritic cells were also featured in several groundbreaking talks that explored the mechanisms through which they recruit T cells and promote immune responses against tumors as well as videos that captured, in stunning detail, the process through which dendritic cells “share” tumor antigens with other immune cells
The final day of AACR18 further reinforced immunotherapy’s rise as well as the challenges in its future: maximizing immunotherapy’s full potential will require a more nuanced understanding of the complexities of the immune system in the context of cancer.
One example of this approach in action was demonstrated by Washington University’s Robert D. Schreiber, Ph.D., who unveiled his team’s recent efforts to analyze, at an unprecedented level, how successful checkpoint immunotherapy impacts the diverse immune cell populations within tumors.
The insights Schreiber focused on most involved macrophages, innate immune cells that are commonly divided into two distinct subtypes, M1 and M2. In his analysis, Schreiber identified five different clusters of macrophages with distinct transcriptional signatures. Interestingly, despite the fact that PD-1 and CTLA-4 checkpoint immunotherapy approaches are largely thought to act directly on T cells, Schreiber found that these treatments, both alone and in combination, remodeled each of the five clusters to different extents, indicating a previously underappreciated role for macrophages in current immunotherapy approaches.
Given macrophages’ ability to “eat” cancer cells as well as facilitate adaptive immune responses by presenting tumor antigens to other immune cells, it doesn’t seem a stretch to suggest that there are important therapeutic insights lurking within these findings. Now, Schreiber’s team is focused on isolating these individual subpopulations of macrophages—and other immune cells—to precisely determine their positive or negative impacts on anti-tumor immune responses.
Schreiber’s talk dovetailed nicely into the closing plenary session that followed, during which AACR president-elect Elaine Mardis, Ph.D., of Nationwide Children's Hospital, discussed the revolutionary impact of next generation sequencing with respect to our understanding of the interactions between tumors and immune cells.
Already, she noted, these tools are providing more personalized approaches against cancer, and are being utilized in the clinic for both prognostic and therapeutic purposes. One prominent example involves identifying patients whose tumors are genomically unstable—referred to as high microsatellite instability, or MSI-hi. These tumors respond especially well to immunotherapy, and that discovery led to the FDA’s historic approval of pembrolizumab for patients with MSI-hi solid tumors, no matter where they’re located.
Mardis also emphasized the importance of complementing the clinical application of existing technologies with continued investments in breakthroughs at the basic research level.
“Basic cancer science is being impacted by technology from many sectors, including computational biology, engineering, and artificial intelligence,” explained Mardis. “These efforts are revealing new and important knowledge that shapes our ability to model cancer as a system.” One such effort is literally developing simplified models of tumors—“cancer-on-a-chip” microdevices—that will allow for circulation and interaction between both tumor cells and immune cells.
Mardis then highlighted the crucial role of data sharing, given the massive amounts of data generated by our ever more detailed investigations. Here too technologies, such as the CRI iAtlas online database, are being developed to ensure that innovative investigations and cutting-edge strategies involving immunotherapy can proceed ahead without being delayed by logistical hurdles.
Johns Hopkins University’s Elizabeth Jaffee, M.D., the current president of AACR, also shined a “spotlight on the convergent science” that will be necessary to overcome the challenges standing in the way of a cure, including efforts to “leverage basic science discoveries to improve translational and clinical research and patient outcomes.”
In his closing plenary talk, City of Hope’s Michael Caliguiri, M.D., the previous president of AACR, doubled down on immunotherapy’s overwhelming presence at AACR18. He highlighted the most impressive results revealed at the conference, almost all of which involved immunotherapy, and then suggested some next steps for immune-based approaches.
According to Caligiuri, the field needs studies designed to “develop predictive biomarkers beyond PD-L1 expression” as well as identify mechanisms that enable tumors to resist immune responses against them. Biomarkers such as PD-L1 and MSI-hi have undoubtedly helped patients by enabling them to be paired with the treatments most likely to help them, but these biomarkers still only apply to a limited number of patients. By discovering and validating new biomarkers, doctors would be able to extend immunotherapy’s benefits to help even more patients.
Caligiuri also stressed the need for more adaptive clinical trial designs, including those that incorporate “novel endpoints that focus on overall survival properties,” which could help ensure that clinical questions are answered in a timely and efficient manner. Additionally, trials evaluating immunotherapy in earlier disease states will help reveal when it might be most effective for any given patient. Given the promising breakthroughs these inquiries could lead to, Caligiuri “hopes to see more trials designed in this way.”
We at the Cancer Research Institute have grown accustomed to the remarkable benefits that it can provide. However, the feeling at AACR18 this year was overwhelming. It was clear that everyone, not just our team and our scientists, was bubbling with excitement at the promise of these immune-based approaches.
What should make everyone more excited and hopeful though, is the realization that—as far as patients should be concerned—immunotherapy’s best days are likely still ahead of us. As we uncover more of cancer’s tricks and simultaneously gain a firmer grasp of the immune system’s capabilities, doctors will only get better at tapping into patients’ most powerful weapon—their own immune systems—to bring this deadly disease under control.