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Under the Microscope: Chimeric Antigen Receptor-Mesenchymal Stromal Cells (CAR-MSCs)

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Olivia Sirpilla
Saad Kenderian
Mayo Clinic
Rochester, MN

Disclaimer/Conflict of interest statement. SK is an inventor on patents in the field of CAR immunotherapy that are licensed to Novartis, Humanigen, MustangBio, and Mettaforge. SSK receives research funding from Kite, Gilead, Juno, BMS, Novartis, Humanigen, MorphoSys, Tolero, Sunesis/Viracta, LifEngine Animal Health Laboratories Inc, and Lentigen. SSK has participated in advisory meetings with Kite/Gilead, Humanigen, Juno/BMS, Capstan Bio, and Novartis. SSK has served on the data safety and monitoring board with Humanigen and Carisma. SK has severed a consultant for Torque, Calibr, Novartis, Capstan Bio, Carisma, and Humanigen. OS and SK are inventors on intellectual property related to the CAR-MSC technology.

Mesenchymal stromal cell (actin cytoskeleton in green) expressing CAR (purple) receptor at the cell surface, where it

detects and engages with target cells to initiate immunosuppressive response.

Rationale of CAR-MSC. CAR equips MSCs with enhanced trafficking through the scFv and their suppressive

functions through the intracellular signaling domains.

What?

CAR-MSCs are engineered allogeneic MSCs equipped with stable expression of chimeric antigen receptors (CARs) for functional therapeutic enhancement. To generate CAR-MSCs, MSCs are engineered with modified lentiviruses to stably express the desired CARs. CAR-MSCs and are then cryopreserved and stored until the time of their off-the-shelf infusion. CAR-MSCs are designed to equip cells to be more effective than non-engineered MSCs in treating autoimmune and degenerative diseases.

Why?

CAR-MSCs overcome two main limitations in current MSC therapeutics: 1) Trafficking to sites of inflammation through the incorporation of a tissue-specific antigen binding domain within the CAR, and 2) Insufficient immunosuppression through the insertion and signal transduction of an immunosuppressive CAR intracellular signaling domain. Applying a functional CAR design to MSCs offers a dynamic way to address issues of limited trafficking, heterogeneity, and inconsistent immunosuppressive efficacy in current MSC clinical trials.

Who?

Adoptive MSC therapy is the most widely studied form of cellular therapy without any current FDA approval. More than 1000 clinical trials for autologous or allogeneic MSC therapy have been carried out for the treatment of immune mediated diseases (1). MSCs represent an attractive cell therapy platform due to their low immunogenicity, regenerative potential and off-the-shelf use. Engineering MSCs with CARs represents a modular novel platform that can be modified and adapted for the treatment of different immune mediated and degenerative diseases.

When?

While the term MSC was first coined in the early 1990s, work on the identification, source, growth kinetics, and biology started in the 19th century. MSCs were first trialed as a cellular therapy in the 1990s as well (2, 3). However, despite their activity in preclinical models, the efficacy of MSCs in treating immune mediated diseases in patients was modest. As a result, several efforts are ongoing to improve the activity and trafficking of MSC, through the modification of culture conditions, MSC priming or engineering (4, 5). Unlike other strategies, CAR engineering of MSCs improves multiple functions within the same product. The invention and development of CAR-MSC started in 2021. The discovery and preclinical studies were published in Nature Biomedical Engineering in April 2024 (6). As a result of this work, a lead construct targeting E-cadherin was developed and optimized for the treatment of graft versus host disease and inflammatory bowel disease. Process development and IND enabling studies were initiated in November 2023, with a target IND submission of early 2025.

Where?

The cellular engineering lab of Dr. Saad Kenderian at the Mayo Clinic in Rochester, Minnesota are pioneering this technology and are the first to generate and introduce CAR-MSCs as a cell therapy product. A proof-of-concept phase I clinical trial in patients with GVHD is planned at Mayo Clinic in Rochester, MN. Following that, plans are to launch a multi-center clinical trial in collaboration with industry (2).

Did you know that…

MSCs are the most clinically studied cell therapy to date without any form of resultant US FDA approval. MSC efficacy in clinical trials has been inconsistent (7). CAR-MSCs overcome many of the challenges with MSC therapy and is a cost-effective off-the-shelf platform for the treatment of immune mediated diseases.

References

Pittenger MF, Discher DE, Peault BM, Phinney DG, Hare JM, Caplan AI. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regen Med. 2019;4:22.
Galipeau J, Sensebe L. Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities. Cell Stem Cell. 2018;22(6):824-33.
Lazarus HM, Haynesworth SE, Gerson SL, Rosenthal NS, Caplan AI. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant. 1995;16(4):557-64.
Hervas-Salcedo R, Fernandez-Garcia M, Hernando-Rodriguez M, Suarez-Cabrera C, Bueren JA, Yanez RM. Improved efficacy of mesenchymal stromal cells stably expressing CXCR4 and IL-10 in a xenogeneic graft versus host disease mouse model. Front Immunol. 2023;14:1062086.
Noronha NC, Mizukami A, Caliari-Oliveira C, Cominal JG, Rocha JLM, Covas DT, et al. Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies. Stem Cell Res Ther. 2019;10(1):131.
Sirpilla O, Sakemura RL, Hefazi M, Huynh TN, Can I, Girsch JH, et al. Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression. Nat Biomed Eng. 2024.
Levy O, Kuai R, Siren EMJ, Bhere D, Milton Y, Nissar N, et al. Shattering barriers toward clinically meaningful MSC therapies. Sci Adv. 2020;6(30):eaba6884.