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

• Published in: Nature communications 2024-04, Vol.15 (1), p.3664-3664, Article 3664
• Main Authors: Joo, Victor, Abdelhamid, Karim, Noto, Alessandra, Latifyan, Sofiya, Martina, Federica, Daoudlarian, Douglas, De Micheli, Rita, Pruijm, Menno, Peters, Solange, Hullin, Roger, Gaide, Olivier, Pantaleo, Giuseppe, Obeid, Michel
• Format: Article
• Language: English
• Subjects: 49/31; 49/47; 631/250/1854/2812; 692/308/575; 692/4028/67/1059/2325; Allografts; Biological Products - pharmacology; Biological Products - therapeutic use; Biopsy; Calcineurin inhibitors; Cancer; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - immunology; CD38 antigen; CD4 antigen; CD69 antigen; CD8 antigen; Cell activation; Cell differentiation; Cytotoxicity; Disease prevention; Everolimus - pharmacology; Everolimus - therapeutic use; Graft rejection; Graft Rejection - immunology; Graft Rejection - prevention & control; Heart transplantation; Heart Transplantation - adverse effects; Herpes viruses; Herpesvirus 1, Human; Humanities and Social Sciences; Humans; Immunological memory; Immunological tolerance; Immunoregulation; Inhibitors; Injection; Lymphocytes; Lymphocytes T; Male; Mammals; Metastases; Middle Aged; MTOR Inhibitors - pharmacology; MTOR Inhibitors - therapeutic use; multidisciplinary; Mycophenolic acid; Oncolysis; Perforin; Prophylaxis; Rapamycin; Rejection; Science; Science (multidisciplinary); Skin Neoplasms - drug therapy; Skin Neoplasms - immunology; Skin Neoplasms - pathology; Skin Neoplasms - therapy; Squamous cell carcinoma; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Therapy; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Transplants & implants
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47965-3

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. Cutaneous squamous cell carcinoma is more frequent and more aggressive in the organ transplanted and represent a therapeutic challenge due to the ongoing transplantrelated immune suppression. Here, the authors present a case report of a patient whose T cell responses were successfully strengthened via primary prophylactic therapy with mammalian target of rapamycin inhibition and intra-lesion injection of the oncolytic herpesvirus T-VEC.