ACGT’s Carl June, MD, discovers counter to T-cell exhaustion for pancreatic cancer

Jan 11, 2022
Devin Golden

Carl June, MD, and his research team at University of Pennsylvania, led the development of chimeric antigen receptor (CAR) T-cell therapies for blood cancers. This breakthrough, supported by Alliance for Cancer Gene Therapy funding, continues to be life-changing and life-saving for many people.

As the focus shifts to solid tumors, Dr. June is again leading the medical community forward to advance curative therapies for patients in need.

Dr. June – a member of Alliance for Cancer Gene Therapy’s Scientific Advisory Council – co-authored an article in the medical publication Cell about overcoming T-cell exhaustion for pancreatic cancer. The news was also published on the Penn Medicine website.

What is the function of CAR T cells?

CAR T cells are engineered T cells extracted from a cancer patient’s blood. Doctors add RNA designed to target specific biomarkers, or antigens, for a type of cancer. T cells are the immune system’s natural defense mechanism, but they often are subdued when fighting cancer. The enhanced engineered T cells are a stronger anti-tumor ally for patients.

This method, which combines gene therapy for cancer with immunotherapy, has been successful in blood cancers such as lymphoma, myeloma, and leukemia, with remission rates increasing significantly. The U.S. Food and Drug Administration (FDA) has approved five CAR T-cell therapies for blood cancers and CAR T cells are one of the leading cancer cell and gene therapies available to patients.

Many experts believe CAR T cells can work for solid tumors as well. However, one of the main obstacles to clincial success is T-cell exhaustion.

What is T-cell exhaustion?

T-cell exhaustion is the natural process of regulating T cells to prevent them from damaging healthy cells or tissue. An objective for improving CAR T-cell therapy is to subdue this exhaustion process to make the T cells strong cancer-fighting machines for longer.

“Exhaustion is triggered in T cells when they have been exposed for too long — on the order of weeks — to their target antigen, as they typically are in the case of solid tumors,” states the report on the University of Pennsylvania website. 

Dr. June finds two biomarkers linked to T-cell exhaustion

Dr. June and colleagues engineered CAR T cells against the protein biomarker mesothelin, which is common on the surface of pancreatic cancer tumors. They exposed the modified T cells to the tumors for four weeks in the laboratory.

Some of the T cells underwent an identity change, reverting to a different type of immune cell called an NK cell. T cells were also exhausted by two proteins – ID3 and SOX4 – which are able to down-regulate genes in immune cells.

Neutralizing these two proteins may preserve the CAR T cells’ anti-cancer effectiveness. The treatment seemed to work even after prolonged exposure to the antigen, when exhaustion usually sets in.

“The study therefore points to a specific strategy — inhibiting ID3 and/or SOX4 — that might help CAR T cells work much better against solid tumors,” Dr. June and his colleagues theorize in the paper.

Dr. June’s accolades in cancer cell and gene therapy

Dr. Carl June talks about his grant in 2004 from Alliance for Cancer Gene Therapy.

Dr. June is championed as one of the most prominent researchers in cell and gene therapy. He received early funding from Alliance for Cancer Gene Therapy, and his research directly led to the first approved CAR T-cell therapies for blood cancers.

His work, and Alliance for Cancer Gene Therapy’s funding, led to the FDA approval of the first T-cell therapy for acute lymphoblastic leukemia. In 2012, he treated the first child with CAR T-cell therapy – Emily Whitehead, who was then a 7-year-old leukemia patient and is today still cancer-free a decade later.

Dr. June has published more than 450 manuscripts and is the recipient of numerous prizes and honors. In addition to his role as an ACGT fellow and ACGT Scientific Advisory Council member, Dr. June holds many professional titles:

  • Professor in Immunotherapy for the University of Pennsylvania’s Department of Pathology and Laboratory Medicine
  • Director of the Center for Cellular Immunotherapies at the Perelman School of Medicine (UPenn)
  • Director of the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania.

Dr. June’s success in developing CAR T cell therapy is evidence of the power of Alliance for Cancer Gene Therapy’s mission, that you can support today with a generous donation. His new findings and ongoing research could lead to innovative, life-saving CAR T-cell and other cell and gene therapies for the approximately 60,000 people diagnosed with pancreatic cancer in the United States each year.

Page sources

  1. New Insights into T-Cell Exhaustion Could Improve Cancer Immunotherapies, Penn Study Finds. Penn Medicine. Retrieved from: Accessed: 12/06/2021.
  2. An NK-like CAR T cell transition in CAR T cell dysfunction. Cell. Retrieved from: An NK-like CAR T cell transition in CAR T cell dysfunction: Cell. Accessed: 12/20/2021.