Combining biophysical properties with co-stimulatory signals to design optimal TCRL/TCR-based CAR T cells

Adoptive cell therapy (ACT) of cancer typically refers to a number of highly personalized approaches which involve the transfer of antitumor immune cells to the individual patient following their manipulation and expansion ex-vivo.

Chimeric Antigenic Receptors (CARs) are hybrid receptors that combine both the humoral and cellular arms of the immune system, by joining the specificity and affinity of an Ab, and the cytolytic and homing abilities of T cells.

The clinical use of CAR-T cells yields impressive clinical responses in the treatment of B cell leukemias and lymphomas. Yet, clinical benefit in other types of cancer, especially solid tumors, is limited, underscoring the need in improving the functional potency of CAR-T cells. In attempt to overcome these limitations, great effort has been put in recent years into optimizing the signaling moieties incorporated into the intracellular portion of CARs, which largely govern the clinical outcome of CAR-T cell therapy.

Based on previous studies in our laboratory, we have hypothesized that incorporating and comparing components of CD28 and 4-1BB costimulatory signaling elements of TCRL-based CARs of different affinities, will uncover the relationship of CAR-Antigen interactions of CD8+T cells in response to tumor antigen challenge.

More precisely, to address the interplay between binding affinity, avidity, antigen density, and downstream signaling and regulatory mechanisms with relation to functional outcome of engineered T cells.

Moreover, the results from understanding the molecular mechanisms that control functional avidity serve to study whether we could modulate functional avidity, which can increase the effectiveness of T-cell based immunotherapies.