Advancement in CAR T Cell Therapy for Patients with Multiple Myeloma Helps Predict Treatment Response and Resistance

Chimeric antigen receptor (CAR) T cell therapy is a recently developed treatment for relapsed or refractory multiple myeloma (MM) and shows success treating multiple other hematological cancers. However, treatment outcomes vary amongst patients. A recent clinical study published in Nature Cancer revealed several biomarkers that enable clinicians to predict patients’ responses and resistance to CAR T cell therapy more accurately. This advancement allows doctors to address and counteract potential side effects prior to treatment, including cytokine release syndrome (CRS) and cytopenia.²

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CAR T therapy modifying T cells outside the body to express CARs, synthetic receptors designed to identify B cell maturation antigen (BCMA) proteins on the surface of cancerous cells. In MM and similar conditions, BCMA proteins are often overexpressed on malignant B cells, making them suitable targets for CAR T cells.² T cells are extracted from the patient through a blood donation, which are then processed and isolated from cancerous cells. These purified T cells are reintroduced into the patient's body via an IV, a process known as leukapheresis. Once infused, the newly modified CAR T cells recognize and target BCMA proteins and other antigens on malignant cells.¹

To assess the effectiveness of CAR T cell therapy in individual patients, researchers from University of Leipzig Medical Center identified biomarkers associated with the treatment efficacy, particularly in MM. Study authors isolated mononuclear cells from peripheral blood and bone marrow samples gathered before and after infusion of BCMA directed CAR T cells and analyzed the individual cells for biomarkers associated with treatment resistance.¹

The research team identified 4 markers consistent with treatment resistance: CD39-Expressing Monocytes, suppressed CD8+ T cell function, natural killer (NK) cell function, and cytotoxic phenotypes of CAR T cells. Study authors found that patients who did not respond to treatment had an immunosuppressive microenvironment characterized by high volumes of white blood cells expressing CD39, suppressed CD8+ T cell, and NK cell function. They also observed that the CAR T cells exhibited phenotypic characteristics, like cytotoxic activity or exhaustion.¹

The study provides evidence that an immunosuppressive microenvironment is the reason for resistance to CAR T cell therapies in patients with MM. Further investigations show the potential of using immunotherapy targets, like programmed cell death protein 1 (PD-1), to improve the function and durability of CAR T cells.¹ Additional studies have also shown that in vivo expansion of CD8+ CAR T cells is associated with positive response to treatment.²

The research team aims to further their investigation of this new data, analyzing more patients who have received CAR T cell therapy to identify additional biomarkers associated with treatment response. “Using state-of-the-art single-cell sequencing, we can now predict whether patients will respond well or less well to CAR T cell therapy before treatment begins,” said PD Dr Merz, Senior Physician at the Department for Hematology, Cell Therapy and Hemostaseology at the University of Leipzig Medical Center, “The aim is to identify the right time for CAR T cell therapy in multiple myeloma at an early stage."³

REFERENCES

1. Rade, M., Grieb, N., Weiss, R. et al. Single-cell multiomic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma. Nat Cancer (2024). https://doi.org/10.1038/s43018-024-00763-8

2. Fischer, L., Grieb, N., Born, P. et al. Cellular dynamics following CAR T cell therapy are associated with response and toxicity in relapsed/refractory myeloma. Leukemia 38, 372–382 (2024). https://doi.org/10.1038/s41375-023-02129-y

3. Biomarkers identified for successful treatment of bone marrow tumors. EurekAlert. April 26, 2024. Accessed May 20, 2024. https://www.eurekalert.org/news-releases/1042702