Treatment of Patients With Metastatic Cancer Using a Major Histocompatibility Complex Class II–Restricted T-Cell Receptor Targeting the Cancer Germline Antigen MAGE-A3
| Autor: | Linda L. Parker, Richard M. Sherry, Steven A. Rosenberg, Yong-Chen Lu, Christopher A. Klebanoff, Stephanie L. Goff, Zhili Zheng, Udai S. Kammula, Mary Ann Toomey, Xin Yao, Steven A. Feldman, Paul F. Robbins, Donald E. White, Yong F. Li, James Chih-Hsin Yang, Pierre van der Bruggen, Tangying Lu |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
CD4-Positive T-Lymphocytes
Male Cancer Research Adoptive cell transfer Time Factors medicine.medical_treatment Receptors Antigen T-Cell Antineoplastic Agents Major histocompatibility complex Immunotherapy Adoptive Transplantation Autologous 03 medical and health sciences 0302 clinical medicine Antigen Antigens Neoplasm Neoplasms Original Reports medicine Cytotoxic T cell Humans Neoplasm Metastasis Antigen-presenting cell HLA-DP beta-Chains Aged biology business.industry Immunotherapy Genetic Therapy Middle Aged Chimeric antigen receptor Neoplasm Proteins Treatment Outcome Oncology 030220 oncology & carcinogenesis Immunology biology.protein Cancer research Interleukin-2 Administration Intravenous Female business CD8 030215 immunology |
| Popis: | Purpose Adoptive transfer of genetically modified T cells is being explored as a treatment for patients with metastatic cancer. Most current strategies use genes that encode major histocompatibility complex (MHC) class I–restricted T-cell receptors (TCRs) or chimeric antigen receptors to genetically modify CD8+ T cells or bulk T cells for treatment. Here, we evaluated the safety and efficacy of an adoptive CD4+ T-cell therapy using an MHC class II–restricted, HLA-DPB1*0401–restricted TCR that recognized the cancer germline antigen, MAGE-A3 (melanoma-associated antigen-A3). Patients and Methods Patients received a lymphodepleting preparative regimen, followed by adoptive transfer of purified CD4+ T cells, retrovirally transduced with MAGE-A3 TCR plus systemic high-dose IL-2. A cell dose escalation was conducted, starting at 107 total cells and escalating at half-log increments to approximately 1011 cells. Nine patients were treated at the highest dose level (0.78 to 1.23 × 1011 cells). Results Seventeen patients were treated. During the cell dose-escalation phase, an objective complete response was observed in a patient with metastatic cervical cancer who received 2.7 × 109 cells (ongoing at ≥ 29 months). Among nine patients who were treated at the highest dose level, objective partial responses were observed in a patient with esophageal cancer (duration, 4 months), a patient with urothelial cancer (ongoing at ≥ 19 months), and a patient with osteosarcoma (duration, 4 months). Most patients experienced transient fevers and the expected hematologic toxicities from lymphodepletion pretreatment. Two patients experienced transient grade 3 and 4 transaminase elevations. There were no treatment-related deaths. Conclusion These results demonstrate the safety and efficacy of administering autologous CD4+ T cells that are genetically engineered to express an MHC class II–restricted antitumor TCR that targets MAGE-A3. This clinical trial extends the reach of TCR gene therapy for patients with metastatic cancer. |
| Databáze: | OpenAIRE |
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