CRI Technology Impact Award recipient Ansuman Satpathy, M.D., Ph.D., at Stanford University is making progress in addressing this challenge. He is building a single-cell atlas to map the genetic factors of T cell dysfunction—factors that contribute to the success or failure of checkpoint immunotherapies when treating cancer patients. Using state-of-the-art genome editing technology, he is able to analyze T cells in each person’s tumor before and after treatment.

“What we saw, at least in basal cell carcinoma, is that immunotherapy recruits a huge new army of T cells to come into the tumor. That’s what appears to be responsible for patient responses, rather than reinvigorating the exhausted T cells,” Dr. Satpathy recounted.

These insights offer a variety of possibilities, such as tracking T cell response to determine dosage. Ultimately, Dr. Satpathy aims to reverse T cell dysfunction to create a durable and effective immune attack against cancer in patients.

A trio of CRI scientists are using another method to tackle this question. By taking clinical insights from patient data back to the lab—a process called reverse translation—they aim to improve outcomes for more patients receiving immunotherapy.

Sumit K. Subudhi, M.D., Ph.D., Padmanee Sharma, M.D., Ph.D., and James P. Allison, Ph.D., SU2C-CRI Immunology Dream Team Investigators at The University of Texas MD Anderson Cancer Center found specific markers among a subset of patients with metastatic, castration-resistant prostate cancer (mCRPC) that may help improve the ability to select patients who may be more likely to respond to treatment with checkpoint blockade.

Unlike melanoma or lung cancer, prostate cancer has relatively fewer gene mutation or associated neoantigens—proteins that are key to our immune system’s ability to recognize and attack cancer. In a study published in Science Translational Medicine, their team demonstrated that some patients may benefit from ipilimumab, a CTLA-4 checkpoint inhibitor, despite fewer mutations in the tumor. These patients had a greater density of cytotoxic and memory T cells in the tumor as well as increased expression of interferon gamma (IFN)-γ, an important immune cell signaling molecule.

A more nuanced understanding of checkpoints and pathways is vital to improving the effectiveness of these treatments. The majority of FDA-approved checkpoint inhibitors target the PD-1/PD-L1 pathway. The protein PD-1 is found on the T cell surface, while PD-L1 is found on the surface of the cancer cell and together they form a checkpoint to stop the T cell from destroying the tumor cell. However, as one CRI fellow discovered, blocking PD-1 does not have the same effect as blocking PD-L1.

Yunlong Zhao, Ph.D., at the University of California, San Diego, compared anti-PD-1 and anti-PD-L1 effectiveness in combination with anti-CTLA-4 immunotherapy. As he described in the journal Immunity, they acted differently on the cell surface, influencing whether CTLA-4 checkpoint blockade would be more or less effective.

These scientists are analyzing the impact of checkpoint immunotherapy on T cells, one of the most dynamic actors in our immune system, but it is not the only immune cell CRI scientists believe offer new potential to help cancer patients. CRI scientists are also exploring other components of the immune system in hope of creating new types of immunotherapy.

Rather than test new drugs or drug combinations in sequence, we can test them simultaneously. Rather than waste time, energy, and money setting up a new trial each time a change needs to be made, “platform trials” can be designed to allow for mid-course corrections. As a result, ineffective treatment strategies can be stopped and the next approach tested, all within the same trial. The impact is tangible: cancer patients are able to receive the most promising immunotherapy treatments without interruption.

The CRI Anna-Maria Kellen Clinical Accelerator’s first platform trial is under way, tackling one of the most common and deadly cancers: prostate cancer. Chaired by Sumit Subudhi, M.D., Ph.D., of The University of Texas MD Anderson Cancer Center, this study is simultaneously evaluating combinations of a checkpoint inhibitor, immunomodulators, a DNA vaccine, an adjuvant, and radiation therapy in patients with metastatic castration-resistant prostate cancer. Called PORTER, the study is the result of a powerful collaboration between CRI and our clinical research partner the Parker Institute for Cancer Immunotherapy along with four different companies and six clinical research sites.

The Clinical Accelerator’s unique nonprofit-academia-industry partnership model and approach to clinical trials has allowed it to adapt quickly to groundbreaking science and shifting circumstances. In the past year, the team has published four new scientific papers, including annual updates on the global landscapes of immuno-oncology, cellular immunotherapies, and PD-1/PD-L1 checkpoint inhibitors. These publications and landscapes not only allow our team to monitor the field and identify opportunities, but they also inform others in the field to reduce inefficiencies and facilitate strategic collaboration.

The Clinical Accelerator team also published a global analysis of the impact of COVID-19 on clinical trials across a range of cancers. The analysis noted that the pandemic had significantly affected patient enrollment in oncology clinical trials in U.S. and Europe to a lesser extent in Asia at time of the survey. Moreover, it showed that 73% of surveyed study leads were avoiding or planning to avoid giving their patients immunosuppressive treatment regimens and 64% were shipping or planning to ship oral drugs directly to patients’ homes rather than administer them during in-person visits.

These clinical trials could not happen without the participation of courageous patients seeking out not only the best treatments for themselves, but also who are willing to contribute to medical research responsible for future breakthroughs.