Primary prophylaxis with mTOR inhibitor enhances T cell effector function and prevents heart transplant rejection during talimogene laherparepvec therapy of squamous cell carcinoma

Victor Joo, Karim Abdelhamid, Alessandra Noto, Sofiya Latifyan, Federica Martina, Douglas Daoudlarian, Rita De Micheli, Menno Pruijm, Solange Peters, Roger Hullin, Olivier Gaide, Giuseppe Pantaleo and Michel Obeid ()
Additional contact information
Victor Joo: Immunology and Allergy Division
Karim Abdelhamid: Oncology Department
Alessandra Noto: Immunology and Allergy Division
Sofiya Latifyan: Oncology Department
Federica Martina: Immunology and Allergy Division
Douglas Daoudlarian: Immunology and Allergy Division
Rita De Micheli: Oncology Department
Menno Pruijm: Nephrology Division
Solange Peters: Oncology Department
Roger Hullin: Cardiology, Cardiovascular Department
Olivier Gaide: Dermatology Division
Giuseppe Pantaleo: Immunology and Allergy Division
Michel Obeid: Immunology and Allergy Division

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract The application of mammalian target of rapamycin inhibition (mTORi) as primary prophylactic therapy to optimize T cell effector function while preserving allograft tolerance remains challenging. Here, we present a comprehensive two-step therapeutic approach in a male patient with metastatic cutaneous squamous cell carcinoma and heart transplantation followed with concomitant longitudinal analysis of systemic immunologic changes. In the first step, calcineurin inhibitor/ mycophenolic acid is replaced by the mTORi everolimus to achieve an improved effector T cell status with increased cytotoxic activity (perforin, granzyme), enhanced proliferation (Ki67) and upregulated activation markers (CD38, CD69). In the second step, talimogene laherparepvec (T-VEC) injection further enhances effector function by switching CD4 and CD8 cells from central memory to effector memory profiles, enhancing Th1 responses, and boosting cytotoxic and proliferative activities. In addition, cytokine release (IL-6, IL-18, sCD25, CCL-2, CCL-4) is enhanced and the frequency of circulating regulatory T cells is increased. Notably, no histologic signs of allograft rejection are observed in consecutive end-myocardial biopsies. These findings provide valuable insights into the dynamics of T cell activation and differentiation and suggest that timely initiation of mTORi-based primary prophylaxis may provide a dual benefit of revitalizing T cell function while maintaining allograft tolerance.

Date: 2024
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DOI: 10.1038/s41467-024-47965-3

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