JUL 11, 2022 3:00 AM PDT

Boosting CAR T Cell Therapy with TIGIT Blockade

WRITTEN BY: Katie Kokolus

Chimeric antigen receptor (CAR) T Cell therapy has emerged as a promising immunotherapeutic approach to treat blood cancers, even leading to long-lasting remission for some advanced cases.  The FDA has approved six CAR T Cell therapies to treat some forms of lymphoma, leukemia, and multiple myeloma. 

T cells, a component of the immune system, carry out the cytotoxic mechanisms of the anti-tumor immune response, which means that they seek out, attack, and kill cancer cells.  T cell receptors (TCR) recognize proteins, called antigens , on the surface of cancer cells, and this recognition activates anti-cancer immune pathways.  Tumors can evade the immune system when TCRs do not adequately recognize antigens on cancer cells. 

CAR T cell therapies consist of specially engineered T cells programmed to recognize cancer and promote immune activation and subsequent cancer cell death.  To generate CAR T cells, doctors harvest a patient’s T cells by drawing blood.  Then, specialized technicians modify the T cells in a laboratory, resulting in a TCR primed to recognize the patient’s cancer.  The CAR T cells are then expanded so that doctors can return large numbers of highly effective immune cells to the patient. 

Source: The National Cancer Institute

While CAR T cell methodology has led to cures in hard-to-treat cancers, only about half, or fewer, patients treated with CAR T cells experience long-term remission.  Thus, identifying mechanisms behind the relapse of CAR T cell-treated cancers is a high priority among cancer researchers.  A study published in Cancer Discovery has uncovered a potential explanation for the reduced remission rates seen in CAR T cell-treated non-Hodgkin lymphoma (NHL). 

One CAR T cell modality used to treat NHL targets CD19, a protein present on lymphoma cells.  This treatment is effective in less than 40% of patients.  The researchers investigated the genetic landscape of CAR T cells following infusion.  Patients provided pre- and post-infusion samples, which researchers analyzed using single-cell sequencing.  The study included 17 patients, 13 responded favorably, and four responded poorly.

The researchers found that non-responding patients exhibited a different exhaustion profile than those who responded.  They identified one marker significantly associated with poor CAR T cell response: TIGIT (which stands for “T cell immunoreceptor with immunoglobulin and ITIM domain”).  The association between poor response and TIGIT suggests it is a viable target for cancer immunotherapy. 

The study also included a pre-clinical component where a mouse model of human NHL was used to assess the potential impact of TIGIT blockade.  The researchers found that blocking TIGIT, in combination with CAR T cells, improved the efficacy of the CAR T cell treatment. 

 

Sources: Nature, Blood Advances, Cancer Discovery, Curr Opinions Oncol, JITC, NCI Visuals Online

About the Author
PhD
PhD in Tumor Immunology. I am interested in developing novel strategies to improve the efficacy of immunotherapies used to extend cancer survivorship.
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