Leick Laboratory

Overview

Redirecting the adaptive immune system, particularly through T cells engineered as chimeric antigen receptor (CAR) T cells, has emerged as a groundbreaking clinical strategy for treating relapsed and refractory malignancies. This approach has shown dramatic responses and even cures in a significant subset of patients. However, most patients undergoing CAR-T cell therapy do not achieve long-lasting anti-tumor responses. The Leick laboratory is dedicated to understanding and overcoming the challenges associated with CAR-T cell therapy. We focus on integrating investigative knowledge of the mechanisms of response, resistance, and toxicity in CAR-T cell patients to design novel methods for enhancing the next generation of CAR-T cell therapies. Through a virtuous cycle of correlation, design, and testing in patients in the context of thoughtful clinical trials, the Leick Lab continually refines CAR-T cell therapies. By applying these findings, we aim to design CAR-T cells that not only extend and enhance patient responses but also minimize adverse effects.

Research Summary

Since the early days of stem cell transplants, when the graft-versus-leukemia effect was first discovered, the remarkable ability of T cells to eradicate malignant cells has been firmly established. In recent years, immune checkpoint antibodies, which block inhibitory signals to endogenous anti-cancer T cells, have emerged as a cornerstone therapy for many solid tumors by non-specifically activating the immune system. However, this approach can lead to significant collateral damage and is constrained by the natural limits of endogenous T-cell targeting machinery. Enter chimeric antigen receptor (CAR) T cell therapy — a revolutionary treatment that combines genetic engineering with novel T cell signaling modulation to target the tumor surfaceome and enhance anti-tumor responses.

The Leick lab is focused on CAR-T cell engineering and clinical translation. Although multiple CAR-T cell therapies have received FDA approval for treating lymphoid malignancies and others have shown promise in solid tumors, most patients currently treated with CAR-T cell therapy will unfortunately not be cured. Nonetheless, we believe these early successes underscore the tremendous potential of CAR-T cell therapy when developed and applied with precision and care.

Our goal is to develop safer, more effective cellular therapies that transform the lives of cancer patients.

Research Focus Areas

Innovative CAR-T Cell Design

Our team leverages cutting-edge insights in immunology, tumor biology, and clinical strategies to develop innovative approaches for enhancing CAR-T cell efficacy. By rationally designing these therapies, we aim to improve their therapeutic potential and patient outcomes.

Tumor Microenvironment Modulation

Suppressive factors within the tumor microenvironment can impede CAR-T cell performance. We use T cells as powerful micro-pharmacies to deliver secreted biologics that target and remodel the immunologic niche. This approach engages other immune cells and augments CAR-T cell potency while avoiding systemic administration of potentially toxic agents, thus expanding the therapeutic window.

Clinical Translation and Trials

While in vitro and in vivo models are invaluable for identifying promising CAR-T cell candidates, they cannot fully replicate the complexity of human physiology. To achieve meaningful progress, we conduct well-designed clinical trials to test innovative strategies directly in patients. Collaborating with Dr. Marcela Maus, Director of the Cellular Immunotherapy Program at MGH, and Dr. Kathleen Gallagher's immune monitoring lab, we develop assays and clinical trials that ensure safe clinical deployment that provide insights into CAR-T cell behavior, fostering a virtuous cycle of continuous improvement.

Deciphering CAR-T Cell Heterogeneity

CAR-T cell therapy is a complex and dynamic field. Unlike traditional pharmacological compounds, CAR-T cells exhibit significant inter- and intra-patient heterogeneity, complicating the understanding of variable patient responses. By utilizing multi-omics approaches with expert collaborators, we explore the genomic, transcriptomic, and proteomic landscapes of CAR-T cells, uncovering novel insights into their mechanisms of action and failure.

Select 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.

Hines MR*, Knight TE*, McNerney KO*, Leick MB*, Jain T, Ahmed S, Frigault MJ, Hill JA, Jain MD, Johnson WT, Lin Y, Mahadeo KM, Maron GM, Marsh RA, Neelapu SS, Nikiforow S, Ombrello AK, Shah NN, Talleur AC, Turicek D, Vatsayan A, Wong SW, Maus MV, Komanduri KV, Berliner N, Henter JI, Perales MA, Frey NV, Teachey DT, Frank MJ, Shah NN. Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome. Transplant Cell Ther. 2023 Jul;29(7):438.e1-438.e438.e16.

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.

Haradhvala NJ*, Leick MB*, Maurer K*, Gohil SH*, Larson RC, Yao N, Gallagher KME, Katsis K, Frigault MJ, Southard J, Li S, Kann MC, Silva H, Jan M, Rhrissorrakrai K, Utro F, Levovitz C, Jacobs RA, Slowik K, Danysh BP, Livak KJ, Parida L, Ferry J, Jacobson C, Wu CJ**, Getz G**, Maus MV**. “Distinct cellular dynamics associated with response to CAR-T therapy for refractory B-cell lymphoma”. Nat Med. 2022 Sep;28(9):1848-1859. 

Leick MB, Maus MV, Frigault MJ. Clinical Perspective: Treatment of Aggressive B Cell Lymphomas with FDA-Approved CAR-T Cell Therapies. Mol Ther. 2021 Feb 3;29(2):433-441. PMID: 33130313

Leick M, Gittelman RM, Yusko E, Sanders C, Robins H, DeFilipp Z, Nikiforow S, Ritz J, Chen YB. T Cell Clonal Dynamics Determined by High-Resolution TCR-β Sequencing in Recipients after Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2020 Sep;26(9):1567-1574

*Equal contribution
** Co-collaborating authors