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Research at Mass General
Marcela V. Maus, MD, PhDAssistant Professor of MedicineHarvard Medical SchoolMass General Cancer Center
Director of Cellular ImmunotherapyMass General Cancer Center
Using the immune system as a cancer treatment has the potential to offer long-term, durable remissions, and perhaps even cures for some patients. The T cells of the immune system are able to specifically kill the target cells they recognize. T cells are also able to persist in the body for many years, and form immune ‘memory,’ which is associated with long-term protection. The Maus laboratory is interested in using genetic engineering techniques to re-direct T cells to find and kill tumor cells while sparing healthy tissues. We aim to: develop new ways to design molecular receptors to target T cells to liquid and solid tumors; use T cells as delivery vehicles for other drugs - or use drugs to help T cells work against tumors; and understand how T cells can work as “living drugs” to treat patients with cancer.
Marcela Maus, MD, PhD
From left to right: Matthew Frigault, Maria Ormhoj, Irene Scarfo and Angela Boroughs
Matthew Frigault and Marcela Maus
From left to right: Matthew Frigault, Ana Castano, Felipe Bedoya, Marcela Maus, Maria Ormhoj, Selena Lorrey, Irene Scarfo, and Angela Boroughs
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 potentiate 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) imageableControl 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. The MGH Cellular Immunotherapy Program directed by Dr. Maus aims to generate a pipeline of genetically engineered CAR T cells to use as “living drugs” in patients with cancer. The program is composed of a “discovery” arm, “manufacturing” and “translational” arms to be able to test genetically-modified T cells in human subjects, and a “clinical/correlative” sciences arm to examine the engraftment, persistence, and bioactivity of T cell products infused into patients. Laboratory members are encouraged to work on a bench->bedside project as well as a bedside->bench project with samples derived from human patients participating in clinical trials of immunotherapy.
Figure: T cells infiltrating glioblastoma tumor in a human subject treated with CAR T cells directed to EGFR variant III. Photo courtesy of MacLean Nasrallah, MD PhD (U. of Pennsylvania).
Maus MV, June CH. Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy. Clin Cancer Res. 2016 Apr 15;22(8):1875-84. PMID: 27084741
Fraietta JA, Beckwith KA, Patel PR, Ruella M, Zheng Z, Barrett DM, Lacey SF, Melenhorst JJ, McGettigan SE, Cook DR, Zhang C, Xu J, Do P, Hulitt J, Kudchodkar SB, Cogdill AP, Gill S, Porter DL, Woyach JA, Long M, Johnson AJ, Maddocks K, Muthusamy N, Levine BL, June CH, Byrd JC, Maus MV. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood. 2016 Mar 3;127(9):1117-27.
Garfall AL, Maus MV, Hwang WT, Lacey SF, Mahnke YD, Melenhorst JJ, Zheng Z, Vogl DT, Cohen AD, Weiss BM, Dengel K, Kerr ND, Bagg A, Levine BL, June CH, Stadtmauer EA. Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma. N Engl J Med. 2015 Sep 10;373(11):1040-7.
Maus MV, Grupp SA, Porter DL, June CH. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood. 2014 Apr 24;123(17):2625-35. Review. PubMed PMID: 24578504.
Johnson LA, Scholler J, Ohkuri T, Kosaka A, Patel PR, McGettigan SE, Nace AK, Dentchev T, Thekkat P, Loew A, Boesteanu AC, Cogdill AP, Chen T, Fraietta JA,Kloss CC, Posey AD Jr, Engels B, Singh R, Ezell T, Idamakanti N, Ramones MH, Li N, Zhou L, Plesa G, Seykora JT, Okada H, June CH, Brogdon JL, Maus MV. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci Transl Med. 2015 Feb 18;7(275):275ra22.PMID:25696001
Beatty GL, Haas AR, Maus MV, Torigian DA, Soulen MC, Plesa G, Chew A, Zhao Y, Levine BL, Albelda SM, Kalos M, June CH. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res. 2014 Feb;2(2):112-20.PubMed PMID: 24579088.
Maus MV, Haas AR, Beatty GL, Albelda SM, Levine BL, Liu X, Zhao Y, Kalos M, June CH. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res. 2013 Jul;1(1):26-31. PubMed PMID: 24777247.
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