Maus Lab

Inaugural Krantz Awards Recipient

2023 Breakthrough Award: Bioengineering CAR T-cell designs for immunotherapy
Team: Max Jan, MD, Robert Manguso, PhD, Marcela Maus, MD, PhD and Debattama Sen, PhD.

Learn more about the team's project and the Krantz Awards

Research Summary

The immune system has become a powerful tool in the fight against cancer. In particular, T cells of the immune system are potent pathogen killers and maintain memory to provide long-term protection for many years. Therefore, using T cells as a cancer treatment has the potential to induce long-term, durable remissions, and perhaps even cure some patients. The Maus laboratory uses 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 and re-direct T cells to target tumors, use T cells as delivery vehicles for other drugs, use drugs to help T cells work against tumors, and understand how T cells can work as “living drugs” to treat patients with cancer. We achieve these goals through translational research, initiating clinical trials with our T cell designs, and learning from how these T cells function in patients.

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 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. Our laboratory focuses on T cell biology and T cell engineering. We design chimeric antigen receptors (CARs) to re-direct T cells to specific antigens. This re- direction 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, application of this therapy to other cancers has not been as successful. We are working to make CAR T cells safe and effective across tumor types.

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

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 “research and discovery” arm that designs and examines the novel CAR T cells, “a regulatory/translational” arm to test the CAR T cells in human subjects, and a “reverse translation” arm to learn how the CAR T cells engraft, persist, and function following infusion into patients. From this knowledge, we then design and evaluate the next generation of CAR T cells that are even more likely to eliminate their target tumor. The reverse translation arm is led by Dr. Kathleen Gallagher, director of our Immune Monitoring Laboratory.

Specifically, the collective goals of the Maus lab are to:

1. Increase CAR T cell efficacy by overcoming tumor-specific challenges using novel engineering strategies.
   We are developing novel types of antigen receptors to target multiple antigens on tumor cells, which improves the elimination of heterogenous tumor cells and prevents antigen-negative relapse while also decreasing the risk of targeting healthy cells. We are also using novel techniques to generate CAR T cells that secrete molecules to enhance CAR T cell function and engage other tumorinfiltrating immune cells.
2. Combine CAR T cells with other drugs to sensitize tumors to T cell-mediated killing, potentiate T cell function, or improve safety.
   Many of the small molecule drugs and antibodies used in the clinic exert their effects on signaling pathways in tumor cells, T cells, and other immune cells. We aim to discover synergistic drug/T cell combinations to increase safety and efficacy, and use genetic engineering tools to confer specific drug sensitivity, resistance, or enhanced molecular switches.
3. Build on the basic biology that drives natural and engineered T cell functions.
   We aim to understand the signaling mechanisms and effector functions used by CAR T cells versus native T cells. We are using high throughput screens to understand genes that regulate CAR T cell function and decipher how tumor cells become or are intrinsically resistant to killing by CAR T cells. We can then better engineer CAR T cells to prevent resistance from occurring.
4. Understand how CAR T cells are functioning in patients.
   After translating our novel CAR T cells from the lab to the clinic, we carefully follow how CAR T cells expand, persist, and/or change phenotype over time in patients. We then correlate this data with patient outcomes and changes in the tumor. Based on these findings, we go back to the lab and redesign CAR T cells to be more effective in patients.
5. Develop improve CAR T cell manufacturing processes.
   Variations in CAR T cell manufacturing regulate their activity in patients, and novel CAR T cell designs require different manufacturing processes compared to CAR T cells currently approved for patients. Our process development lab is working to streamline the manufacturing of novel CAR T cells while also striving to make CAR T cells more readily available to patients.

Publications

Selected Publications

Choi BD, Gerstner ER, Frigault MJ, Leick MB, Mount CW, Balaj L, Nikiforow S, Carter BS, Curry WT, Gallagher K, Maus MV. Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma. N Engl J Med. 2024 Apr 11;390(14):1290-1298.

Korell F, Olson ML, Salas-Benito D, Leick MB, Larson RC, Bouffard A, Silva H, Gasparetto A, Berger TR, Kann MC, Mergen M, Kienka T, Wehrli M, Haradhvala NJ, Bailey SR, Letai A, Maus MV. Comparative analysis of Bcl-2 family protein overexpression in CAR T cells alone and in combination with BH3 mimetics. Sci Transl Med. 2024 Jun 5;16(750):eadk7640.

Frigault MJ, Graham CE, Berger TR, Ritchey JK, Horick N, El-Jawahri A, Scarfò I, Schmidts A, Haradhvala N, Wehrli M, Lee WH, Parker A, Wiggin HR, Bouffard AA, Dey A, Leick MB, Katsis K, Elder EL, Dolaher M, Cook D, Chekmasova AA, Huang L, Nikiforow S, Daley H, Ritz J, Armant M, Preffer F, DiPersio JF, Nardi V, Chen YB, Gallagher KME, Maus MV. Phase 1 study of CAR-37 T cells in patients with relapsed or refractory CD37+ lymphoid malignancies. Blood. 2024 May 23:blood.2024024104.

Leick MB, Silva H, Scarfò I, Larson R, Choi BD, Bouffard AA, Gallagher K, Schmidts A, Bailey SR, Kann MC, Jan M, Wehrli M, Grauwet K, Horick N, Frigault MJ, Maus MV. Non-cleavable hinge enhances avidity and expansion of CAR-T cells for acute myeloid leukemia. Cancer Cell. 2022 May 9;40(5):494-508.e5.

Larson RC, Kann MC, Bailey SR, Haradhvala NJ, Llopis PM, Bouffard AA, Scarfó I, Leick MB, Grauwet K, Berger TR, Stewart K, Anekal PV, Jan M, Joung J, Schmidts A, Ouspenskaia T, Law T, Regev A, Getz G, Maus MV. CAR T cell killing requires the IFNγR pathway in solid but not liquid tumours. Nature. 2022 Apr;604(7906):563-570.

Group Members

• Alexander Armstrong
• David Bargiela, MD, PhD
• Trisha Berger, PhD
• Filippo Birocchi, PhD
• Viktoria Blumenberg, MD
• Amanda Bouffard
• Alexandra Bratt
• Diane Brunett
• Raihan Chowdhury, PhD
• Eli Darnell, MD
• Magdi Elsallab, MD, PhD
• Giulia Escobar, PhD
• Yueyang Fan*
• Jessica Frank*
• Kathleen Gallagher, PhD
• Andrea Garmilla**
• Charlotte Graham, MD, PhD
• Deshea Harris, MS
• Cassidy Ho
• Lu Huang, PhD
• Andrew Hwang
• Christopher Kelly
• Tamina Kienka**
• Maxx King
• Benjamin Mantarian, MBA
• Adele Mucci, PhD
• Sophie Nigrovic
• Aiyana Parker
• Merle Phillips*
• Diego Salas-Benito, MD, PhD
• Steven Sangwoo Park, PhD
• Emily Schneider**
• Emily Silva, MS
• Xiameng Sun
• Hana Takei
• Zandra Walton, MD, PhD

* PhD Candidate
**MD Candidate