Marcela V. Maus, MD, PhD

Maus Lab

The goal of the Maus lab is to design and evaluate next generation genetically-modified (CAR) T cells as immunotherapy in patients with cancer.

Overview

Marcela V. Maus, MD, PhD
Assistant Professor of Medicine
Harvard Medical School
Mass General Cancer Center

Director of Cellular Immunotherapy
Mass General Cancer Center

Research Summary

Using the immune system as a cancer treatment has the potential to induce 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 enables the possibility of 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, and use drugs to help T cells work against tumors; and understand how T cells can work as “living drugs” to treat patients with cancer.

Group Members

Marcela V. Maus, MD, PhD

Principal Investigator

Group Members

  • Felipe Bedoya, PhD
  • Angela Boroughs*
  • Amanda Bouffard
  • Ana Castano, MD
  • Bryan Choi, MD, PhD
  • Matthew Frigault, MD
  • Madison M. Hebert
  • Rebecca Larson*
  • Selena Lorrey*
  • Maria Ormhoj*
  • Lauren Riley
  • Irene Scarfo, PhD
  • Xiaoling Yu**

*PhD Candidate
**MD Candidate

Research Projects

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-1 monoclonal 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. Contain molecular improvements in receptor design to enhance specificity, potency, and safety.

    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. In liquid tumors, it will also be important to improve the safety of CAR T cells, while in solid tumors, the focus is on increasing their potency.

  2. 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.

  3. Have additional modifications that make CAR T cells (a) resistant to inhibitory mechanisms, (b) imageable, or (c) more feasible to manufacture and administer.

    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.

  4. We aim to understand the basic biology and mechanisms that drive engineered T cell function.

The Mass General 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: CAR T cells (co-expressing the red fluorescent marker mCherry) surrounding and killing glioblastoma cells (expressing green fluorescent protein).

Select Publications

O’Rourke, D.M. Nasrallah, M.P., Desai, A., Melenhorst, J.J., Mansfield, K., Morrissette, J.J.D., Martinez-Lage, M., Brem, S., Maloney, E., Shen, A., Isaacs, R., Mohan, S., Plesa, G., Lacey, S.F., Navenot, J-M., Zheng, Z., Levine, B.L., Okada, H., June, C.H., Brogdon, J.L., Maus, M.V. A single dose of peripherally-infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. 2017 Jul 19;9(399).

Ormhoj, M., Bedoya, F., Frigault, M.J., Maus, M.V. CARs in the lead against multiple myeloma. Current Hematologic Malignancy Reports. April 2017; 40(3): 104-107.

Scarfo, I., Maus, M.V. Current approaches to increase CAR T cell potency in solid tumors: targeting the tumor microenvironment. J Immunother. March 21, 2017.

Bedoya, F., Frigault, MJ, Maus, M.V. The flipside of the power of engineered T cells: observed and potential toxicities of genetically modified T cells as therapy. Mol Ther. 2017, Feb 1; 25(2):314-320.

Frigault MJ, Maus MV. Chimeric antigen receptor-modified T cells strike back. International Immunology. 2016 Jul;28(7):355-63.

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.

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.

Video

Marcela V. Maus, MD, PhD, Director of the Cellular Immunotherapy Program at the Mass General Cancer Center, was awarded a 2017 Stand Up to Cancer Innovative Research Grant for her work on Potentiating Novel Engineered Cellular Therapies for Solid Tumors.

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