Explaining TCR therapy on heels of KIMMTRAK approval

T cells (dark blue) are shown fighting melanoma cells (red) after KIMMTRAK treatment. Photo courtesy of Cancers.

KIMMTRAK^® made history on January 26, 2022 as the first FDA-approved T-cell receptor (TCR) therapeutic for uveal melanoma, a rare type of melanoma occurring in the eye.

The immunotherapy, manufactured by the biotech company Immunocore, is also the first cancer cell and gene therapy approved in the United States for any type of solid tumor cancer. KIMMTRAK is the brand name of the generic drug tebentafusp-tebn.

However, it’s not the first cancer cell and gene therapy approved for any type of cancer. CAR T-cell therapy broke through for blood cancer with the first FDA approval in 2017. KYMRIAH® (tisagenlecleucel) was approved for children and young adults with acute lymphoblastic leukemia with initial funding by Alliance for Cancer Gene Therapy.

CAR T-cell therapy and T-cell receptor therapy are not quite the same – although they are similar in many ways. Alliance for Cancer Gene Therapy explains how TCR therapies work and why they are different from the other well-known cancer cell and gene therapy.

What is CAR T-cell therapy?

CAR stands for chimeric antigen receptors, which are a genetic code enhancement to extracted T cells. This genetic code, a type of gene therapy, helps the T cells target cancer cells with a specific protein biomarker. One of the challenges with CAR T-cell therapies is the biomarker target can be in healthy tissue, meaning CAR T cells can attack and kill necessary healthy cells along with cancer cells.

There are already five CAR T-cell therapies approved for specific types of blood cancer. Aside from KYMRIAH, the other four are:

• YESCARTA® (axicabtagene ciloleucel) for non-Hodgkin lymphoma
• TESCARTUS® (brexucabtagene autoleucel) for mantel cell lymphoma
• BREYANZI® (lisocabtagene maraleucel) for types of non-Hodgkin lymphoma
• ABECMA® (idecabtagene vicleucel) for multiple myeloma

What is TCR therapy?

Engineered TCRs are similar to CAR T cells in being a next-generation cell therapy: T cells are extracted from a patient and enhanced in a lab to attach a receptor enabling them to attack the cancer cells. A major difference is engineered TCRs target specific proteins or antigens only linked to proteins that mark cancer cells.

T-cell receptor therapy accomplishes this by looking for a human leukocyte antigen (HLA), which is integral to presenting cancerous antigens to T cells. HLA is part of the major histocompatibility complex (MHC), which includes fragments of proteins called peptides.

When these peptides are from a cancerous protein, HLA presents them to the engineered T-cell receptors. The T cells then go on the attack, now alert to the abnormal peptide which is not present on healthy cells.

How KIMMTRAK treats uveal melanoma

The process explained above is how T-cell receptor therapies like KIMMTRAK go deeper into the tumor microenvironment to single out cancer cells from healthy tissue. 

For KIMMTRAK, the HLA target approved by the FDA for melanoma is A*02:01, which presents the melanoma antigen gp100 to T cells. KIMMTRAK helps the engineered T cells seek out  gp100 via A*02:01. KIMMTRAK is a novel bispecific protein comprised of a soluble T-cell receptor fused to an anti-CD3 immune-effector function. KIMMTRAK specifically targets gp100, a lineage antigen expressed in melanocytes and melanoma.

A scientific article published by the American Association for Cancer Research found that gp100 was only detectable on HLA-A*02:01-positive melanoma cells. The research supports using an engineered T-cell receptor for this specific HLA.

Alliance for Cancer Gene Therapy is a thought-leader in cancer cell and gene therapy research and treatment. Our mission includes funding development and increasing awareness of cell and gene therapies, including providing explanations of how each one works to slow or stop tumor growth and improve survival rates. The Alliance funded the initial science that led to CAR T-cell therapy FDA approvals for blood cancers, setting the stage for the wealth of cell and gene therapy research within hundreds of companies and institutions today.

With your financial contribution, we can improve the chances of other cancer cell and gene therapy approvals in the near future. Please join our Alliance today and do your part to fund the research that helps save lives.