Checkpoint immunotherapies—which unleash immune cells so that they can eliminate tumors—have revolutionized cancer treatment over the past several years. Since 2011, they’ve been approved for over 20 different cancer types, according to Elizabeth M. Jaffee, M.D., who serves on the Cancer Research Institute (CRI) Scientific Advisory Council and chaired day three’s plenary session, “The Immune System and Cancer.”
This success “came from understanding fundamental mechanisms of T cell activation and regulation,” proclaimed James P. Allison, Ph.D., director of the CRI Scientific Advisory Council and a co-leader of the SU2C-CRI Cancer Immunology Translational Research Dream Team at the University of Texas MD Anderson Cancer Center.
Dr. Allison, who pioneered the first FDA-approved checkpoint immunotherapy, the anti-CTLA-4 checkpoint immunotherapy Yervoy® (ipilimumab, noted that more than 70,000 patients have already received the drug, and while not all patients respond, those who do typically experience more durable and longer-term responses.
Anti-PD-1 checkpoint immunotherapies, such as Opdivo® (nivolumab) and Keytruda® (pembrolizumab), have also helped many patients with advanced cancer. In trials where patients received a combination of Yervoy and Opdivo, the two together appear to work better than either alone because they target different pathways and work on different time scales (Opdivo works rapidly, while Yervoy’s effects can take a little longer).
To improve the effectiveness of these therapies, Dr. Allison and his team have sought to better understand fundamental mechanisms associated with each of these treatments. One investigation led by Stephen Mok, Ph.D., a CRI-funded postdoctoral fellow in Dr. Allison’s lab, aims to figure out how these treatments affect immune memory.
In mice, Dr. Mok found that anti-CTLA-4 treatment by itself provided better protection and increased expression of genes associated with immune activation and memory, compared to anti-PD-1 treatment by itself. Furthermore, he found that responses to each of these treatments relied primarily on different types of T cells during priming, thus providing another rationale for combining these immunotherapies.
Later, Drew M. Pardoll, M.D., Ph.D., a member of the CRI Scientific Advisory Council and a leader of the SU2C-CRI Cancer Immunology Translational Research Dream Team at Johns Hopkins Medicine, spoke about his team’s efforts to understand the mechanisms behind anti-PD-1 checkpoint immunotherapy responses.
Dr. Pardoll first highlighted a tool called MANAFEST (Mutation Associated NeoAntigen Functional Expansion of T cells), which enables his team to precisely characterize mutated tumor proteins that trigger T cell responses. Then, with the ImmunoMap algorithm, they can determine the “quality” of this anti-tumor T cell repertoire.
Employing these tools in a clinical trial, they analyzed patients before and after anti-PD-1 immunotherapy and observed rapid expansion of tumor-specific T cells after treatment, even in some patients whose tumors had relatively few mutations. In one lung cancer patient whose tumor had shrunk by more than 90 percent after treatment with Opdivo, they found new tumor-specific T cells—dying pieces of tumor effectively became a kind of “vaccination.”
Whereas Dr. Pardoll’s anti-PD-1 approach “vaccinated” patients indirectly, Nir Hacohen, Ph.D., a CRI-funded CLIP investigator at the Broad Institute of MIT and Harvard, is taking a more direct approach that he hopes will “take the luck out of checkpoint immunotherapy.”
Dr. Hacohen’s vaccines consist of 20 mutated peptides derived from patients’ individual tumors. So far his team has treated six patients—all with advanced melanoma—with vaccines and the immune adjuvant Hiltonol® (Poly-ICLC), and significant CD4+ (“helper”) and CD8+ (“killer”) T cell responses were seen in all patients. These T cells were able to eliminate tumor cells as well as express metabolic and growth-associated genes important to immune cell proliferation and trafficking.
While two patients progressed after receiving the vaccine, both achieved complete responses after subsequent anti-PD-1 treatment, highlighting the persistence and enhanced breadth of anti-tumor T cell responses stimulated by these complementary immunotherapies.
However, there’s still a need for a better peptide selection process. To address that, Dr. Hacohen’s team is now using neural network models and training them to predict the best peptide candidates for incorporation into individual patient vaccines, which will hopefully improve the effectiveness of this approach.
In our next blog post, we will cover some of the large-scale immunotherapy clinical trial results presented at AACR17.