Research areas

The research group has several current areas of research. Here you can read more about these.

Targeting of cancer-specific mutations

Immunotherapy with checkpoint inhibitors, such as anti-PD1 and anti-CTLA4, activates T-cells capable of recognizing peptides from mutated proteins (neo-antigens), representing a major breakthrough in cancer treatment.

However, while all cancers harbor mutations, patient T-cells rarely elicit a curative response and the majority of patients eventually relapse following checkpoint inhibition. It is now clear that patient T-cells only recognize a minor subset of mutations in a tumor.

A major focus of the lab is to develop novel technologies that can improve on the identification and targeting of cancer-specific mutations that can evoke an immune response (immunogenic neoantigens). Our goal is to use such technologies to improve on the therapeutic outcome of patients treated with immunotherapy.
 

Targeting of self-antigens

Therapeutic antibodies recognize "normal" cell surface proteins with cell type-restricted expression. A good example is antibodies to the B-cell antigen CD20, used for treatment of leukemia and lymphoma. These antibodies kill normal and malignant B cells indiscriminately. Yet, the ability to limit cytotoxicity to a single cell type represents an important step forward compared to chemotherapy and radiation therapy.

The major advantage of self-antigens as therapeutic targets (relative to cancer mutations) is that the same target can be used in all patients with a particular cancer type. Similarly, CARs (chimeric antigen receptors) target normal cell surface proteins like CD19 to which the antibody portion of the receptor binds.

Adoptive cell therapy using T-cells genetically equipped with CARs has been a tremendous success in the treatment of B-lymphoid leukemia and lymphoma. However, in spite of worldwide efforts it has proved difficult to find similarly good targets in other leukemias, and in other cancer types.

The number of candidate self-antigens that could be targeted in cancer can be increased dramatically with the use of T-cell receptors as alternatives to CARs in adoptive cell therapy. The reason is that T-cells, in contrast to CARs/antibodies, have the ability to recognize peptides from intracellular proteins, and the large majority of cellular proteins are inside the cell.

A major focus in our group is to direct T-cell receptors to peptides derived from self-antigens expressed on cancer cells by use of foreign (allogeneic) HLA for antigen presentation.
 

Profiling of T-cell receptors

The T-cell repertoire serves as a “fingerprint” of the immune response, and can reveal information about the nature of the antigens eliciting a T-cell response.

In collaboration with clinical collaborators, we have used the profiles of T-cell repertoires of patients with multiple sclerosis and with autoimmune liver disease to elucidate characteristics of targets of T cells in these diseases.

Published Oct. 14, 2019 1:43 PM - Last modified Oct. 14, 2019 1:43 PM