Focus on faculty research: Adekunle Odunsi, MD, PhD

On March 1, 2021, Adekunle Odunsi, MD, PhD, FRCOG, FACOG, succeeded Michelle Le Beau, PhD, as director of the University of Chicago Medicine Comprehensive Cancer Center. Odunsi is also the AbbVie Foundation Director and the Biological Sciences Division’s Dean for Oncology. Prior to joining the University of Chicago, he held many prestigious leadership positions, including his previous role as Deputy Director of the Roswell Park Comprehensive Cancer Center and Executive Director of the Center for Immunotherapy at Roswell Park in Buffalo, New York. Despite his many hats, he has remained active in basic, translational, and clinical cancer research.

Odunsi’s approach to fighting cancer centers on exploiting the body’s adaptive immune response, which is specific to an encountered pathogen, as opposed to the innate immune response which employs a non-specific defense. Odunsi and colleagues began by studying antigens (molecular flags that signal a specific threat to immune cells, such as T cells) associated with tumor cells, and they specifically looked for antigens which are shared across many people. The team identified a particular “cancer/testis antigen” known as NY-ESO-1, which is expressed by a wide range of cancer types but in no other normal, healthy tissue except for the adult male testes.

“The potential for off-target toxicity, when you target NY-ESO-1 with immunotherapy, is limited,” said Odunsi. Because the testes are “immunologically privileged,” meaning that they are not easily attacked by the immune system, this approach is not a threat to healthy tissue there either.

After the discovery of NY-ESO-1’s unique ability to act as a flag for a broad range of cancer cell types and not healthy tissue, Odunsi and collaborators began testing vaccines against NY-ESO-1 in ovarian cancer patients. While the group saw vaccine-induced responses that prolonged remission, several patients eventually developed recurrent or progressive disease. To combat this, Odunsi’s team turned to engineering T cells with unique receptors that could more effectively recognize the NY-ESO-1 antigens. But they also found that some tumors do not express NY-ESO-1 in a spatially uniform way, and that others actively shut down the expression of NY-ESO-1 during an immune attack. This means that even a specialized immune system may only identify and attack certain areas within a tumor, while ignoring others. Odunsi’s research team therefore began work on how to enforce the uniform expression of NY-ESO-1.

Altogether, by employing methodical, rigorous research methods and being open to new discoveries along the way, Odunsi and his team have made remarkable strides in understanding our immune system and its relationship to cancer.

“The primary mechanism by which NY-ESO-1 expression is regulated is a process called DNA methylation,” explained Odunsi. When the researchers used de-methylating drugs, they found it induced expression of NY-ESO-1 in cancerous tissue, again leaving healthy tissue unaffected. Odunsi and his research team believe this work has great potential for treating cancer in patients, and are currently continuing this research and developing clinical trials at the University of Chicago.

At the same time, Odunsi’s lab realized that even perfectly engineered T cells, with access to an abundance of uniformly distributed antigens, could be restricted in their efficacy by their limited lifespan.

“The lack of T cell persistence is a major gap in the field of adoptive T-cell therapy,” said Odunsi. “Typically, within 60 to 90 days of giving cell therapy, those cells are gone.”

Despite this gap, scientists know that T cell persistence time is related to both the degree of cell differentiation (how much the gene expression of a cell has changed over time) and the cell’s ability to withstand the hostile environment immediately surrounding a tumor (the tumor “microenvironment”). With this knowledge, the team devised a novel strategy of programming a certain type of stem cell, which, once back in the body, becomes a long-lasting source of engineered T cells. Those T cells themselves are programmed to be resistant to immune-suppressive proteins, called cytokines, produced by the tumor. Together, these “next-generation” approaches are likely to prolong cancer remission rates.

Another approach Odunsi and colleagues are taking to increase T cell efficacy is to understand the mechanisms by which T cells acquire tissue residency.

“Ideally, if a T cell has made it to the tumor microenvironment and survived there, you want it to stay and continue the good fight,” explains Odunsi.

In reality, the cell may leave, recirculating through the body. By studying certain kinds of cells which do tend to stick around longer, Odunsi’s team has identified some of the key mechanisms by which cells can acquire tissue residency. At the University of Chicago, Odunsi plans to implement this new understanding in clinical trials by utilizing engineered T cells with enhanced potential for residency at tumor sites.

Altogether, by employing methodical, rigorous research methods and being open to new discoveries along the way, Odunsi and his team have made remarkable strides in understanding our immune system and its relationship to cancer. Although nothing in biology or medicine is ever simple, Odunsi’s research directions remain focused by keeping in mind the goal of testable health outcomes and following the science. He is looking forward to continuing his research on enhancing T cell persistence and resilience, including in new clinical trials at the University of Chicago Medicine.