Immunology Faculty Member - Marcela Maus, PhD

Marcela Maus, PhD




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Tel: 617-726-5619
Email: mvmaus@mgh.harvard.edu



Immune therapies that engage T cells have the potential to induce long-term durable remissions of cancer. In hematologic malignancies, allogeneic hematopoietic stem cell transplant can be curative in part due to T-cell mediated anti-tumor immunity; in solid tumors, checkpoint blockade with anti-CTLA-4 or anti-PD-1monoclonal antibodies can mediate long-term responses by releasing T cells from tightly controlled peripheral tolerance. Chimeric antigen receptors (CARs) are synthetic molecules designed to re-direct T cells to specific antigens. Re-directing T cells with CARs is an alternative method of overcoming tolerance and has shown great promise in the clinical setting for B cell malignancies such as adult and pediatric acute lymphoblastic leukemia (ALL). This therapy is so effective in ALL that based on relatively small numbers of patients, multiple academic centers and their industry partners have received Breakthrough Designation from the FDA to commercialize CAR T cell products. However, successful application of this form of therapy to other cancers is likely to require refinements in the molecular and clinical technologies.
The goal of the Maus lab is to design and evaluate next generation genetically-modified (CAR) T cells as immunotherapy in patients with cancer.
Specifically, next generation T cells that the Maus lab intends to develop includes CAR-T cells that
(1) are administered in combination with other drugs delivered either (a) systemically or (b) as payloads attached to T cells to sensitize tumors to T cell mediated killing and/or potentiate T cell function
Some recently developed targeted therapies have effects on T cells or tumor cells that potentiates the tumor-killing effects. Alternatively, T cells can be chemically or genetically loaded with drugs to potentiate T cell function, such as cytokines or antibodies to checkpoint inhibitors. In this case, re-directed T cells could be used as a delivery mechanism to target an otherwise toxic drug specifically to the tumor.
(2) have additional modifications that make CAR T cells (a) resistant to inhibitory mechanisms, and/or (b) imageable
Control of T cell function is a complex process orchestrated by a variety of molecules, some of which deliver inhibitory signals. Tumors often express ligands to inhibit T cell function. Using a single vector, genetically modified T cells can be re-directed not only to recognize a new antigen on tumor cells, but also to be resistant to the inhibitory tumor micro-environment. Similarly, it is possible to have T cells encode a protein that makes them imageable with techniques such as PET or MRI.
(3) contain molecular improvements in receptor design to enhance specificity
Most chimeric antigen receptors used to re-direct T cells to a new target are based on enforcing expression of either murine single-chain antibody fragments, natural ligands, or natural T cell receptors. However, novel types of antigen receptors are in development and could be exploited to re-direct T cells such that they can distinguish between antigen expressed on the tumor and the same antigen expressed in healthy tissues.



Last Update: 10/27/2015



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