Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma
Gerald P Linette1, Edward A Stadtmauer, Marcela V Maus
1Siteman Cancer Center and Departments of Medicine and Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Abstract:
An obstacle to cancer immunotherapy has been that the affinity of T-cell receptors (TCRs) for antigens expressed in tumors is generally low. We initiated clinical testing of engineered T cells expressing an affinity-enhanced TCR against HLA-A*01-restricted MAGE-A3. Open-label protocols to test the TCRs for patients with myeloma and melanoma were initiated. The first two treated patients developed cardiogenic shock and died within a few days of T-cell infusion, events not predicted by preclinical studies of the high-affinity TCRs. Gross findings at autopsy revealed severe myocardial damage, and histopathological analysis revealed T-cell infiltration. No MAGE-A3 expression was detected in heart autopsy tissues. Robust proliferation of the engineered T cells in vivo was documented in both patients. A beating cardiomyocyte culture generated from induced pluripotent stem cells triggered T-cell killing, which was due to recognition of an unrelated peptide derived from the striated muscle-specific protein titin. These patients demonstrate that TCR-engineered T cells can have serious and not readily predictable off-target and organ-specific toxicities and highlight the need for improved methods to define the specificity of engineered TCRs.
Insights
Engineered T cells targeting cancer showed unexpected heart damage and death in patients. This highlights risks of off-target toxicity and the need for better specificity testing in T-cell therapies.
Area of Science:
- Immunology
- Oncology
- Cardiology
Background:
- Low T-cell receptor (TCR) affinity for tumor antigens is a challenge in cancer immunotherapy.
- Engineered T cells with enhanced TCRs are being developed to overcome this limitation.
Purpose of the Study:
- To assess the safety and efficacy of engineered T cells with an affinity-enhanced TCR targeting MAGE-A3 in patients with myeloma and melanoma.
- To investigate the cause of unexpected severe adverse events observed during clinical trials.
Main Methods:
- Open-label clinical testing of TCR-engineered T cells in patients with myeloma and melanoma.
- Autopsy gross findings and histopathological analysis of myocardial tissue.
- In vitro T-cell killing assays using cardiomyocyte cultures derived from induced pluripotent stem cells.
Main Results:
- Two patients experienced fatal cardiogenic shock post-T-cell infusion, with severe myocardial damage and T-cell infiltration at autopsy.
- No MAGE-A3 expression was found in heart tissues; engineered T cells proliferated robustly in vivo.
- T cells killed cardiomyocyte cultures by recognizing a titin-derived peptide, indicating off-target recognition.
Conclusions:
- TCR-engineered T cells can cause severe, unpredictable off-target organ toxicities, specifically cardiac damage.
- Improved methods are crucial for defining engineered TCR specificity to mitigate risks before clinical application.
More Related Videos
09:15Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
06:25Ex Vivo Culture of Circulating Tumor Cells in the Cerebral Spinal Fluid from Melanoma Patients to Study Melanoma-Associated Leptomeningeal Disease
Published on: March 29, 2024
