Maus Lab

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.

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 transplants can be curative, in part due to T-cell mediated anti-tumor immunity. In solid tumors, checkpoint blockades 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 leukemia and lymphoma. 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 geneticallymodified (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 tumorkilling 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.
4. We aim to understand the basic biology and mechanisms that drive engineered T cell function.
   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 “research and discovery” arm, “a regulatory/ translational” arm to be able to test genetically-modified T cells in human subjects, and a “clinical/ correlative” sciences arm of immune profiling to examine the engraftment, persistence, and bioactivity of T cell products infused into patients. The Immune Monitoring Laboratory is directed by Dr. Kathleen Gallagher.

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.

Publications

Selected Publications

Boroughs AC, Larson RC, Choi BD, Bouffard AA, Riley LS, Schiferle E, Kulkarni AS, Cetrulo CL, Ting D, Blazar BR, Demehri S, Maus MV. Chimeric antigen receptor costimulation domains modulate human regulatory T cell function. JCI Insight, March 2019.

Kleinstiver BP, Sousa AA, Walton RT, Tak YE, Hsu JY, Clement K, Welch MM, Horng JE, Malagon-Lopez J, Scarfò I, Maus MV, Pinello L, Aryee MJ, Joung JK. Engineered CRISPR-Cas12a variants with increased activities and improved targeting ranges for gene, epigenetic and base editing. Nat Biotechnol. 2019 Mar;37(3):276-282.

Scarfo I, Ormhoj M, Frigault M, Castano AP, Lorrey S, Bouffard AA, van Scoyk A, Rodig SJ, Shay AJ, Aster JC, Preffer FI, Weinstock DM, Maus MV. Anti-CD37 chimeric antigen receptor T cells are active against B and T cell lymphomas. Blood. 2018 Oct 4;132(14):1495-1506.

Tang L, Zheng Y, Bandeira de Melo M, Mabardi L, Castano AP, Xie Y-Q, Na L, Kudchodkar SB, Wong HC, Jeng EK, Maus MV, Irvine DJ. Enhancing T cell therapy through TCR signalingresponsive nanoparticle drug delivery. Nat Biotechnol, September 2018; 36 (8): 707-716.

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.

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).

Group Members

• Stephanie Bailey, PhD
• Amanda Bouffard
• Wilfredo Garcia Beltran, MD, PhD
• Genevieve Gerhard**
• Max Jan, MD, PhD
• Michael Kann
• Rebecca Larson*
• Mark Leick, MD
• Pedro Ojedao†
• Maria Cabral Rodriguez
• Irene Scarfo, PhD
• Andrea Schmidts, MD
• Maegan Sheehan
• Emily Silva
• Aarti Ambike Svirastavao†
• Sonika Vatsa

†Masters candidate
*PhD Candidate
**MD Candidate