Abstract CT003: A phase I study of an HLA-DPB1*0401-restricted T-cell receptor targeting MAGE-A3 for patients with metastatic cancer
Authors: Lu Yong-Chen , Parker Linda L. , Lu Tangying , Zheng Zhili , Yao Xin , Robbins Paul F. , Feldman Steven A. , van der Bruggen Pierre , Klebanoff Christopher A. , Hinrichs Christian S. , Goff Stephanie L. , Sherry Richard M. , Kammula Udai S. , Yang James C. , Rosenberg Steven A. 
Published: July 2016

Background: Adoptive transfer of genetically-modified T cells is being explored as a salvage treatment for patients with selected metastatic cancers. Most of the current strategies utilize MHC class I-restricted T cell receptor (TCR) or chimeric antigen receptor (CAR) technologies to genetically modify CD8+ T cells or bulk T cells for patient treatment. Evidence indicates that CD4+ T cells can induce tumor regression, similar to CD8+ T cells. To test this hypothesis, an HLA-DPB1*0401-restricted TCR recognizing MAGE-A3 was isolated from a patient's peripheral blood after MAGE-A3 peptide vaccination. Because HLA-DPB1*0401 is present in ∼60% of the Caucasian population and MAGE-A3 is expressed in up to one third of tumor specimens from a variety of cancer types, this TCR immunotherapy could potentially be applicable for a significant portion of cancer patients.

Trial Design: Eligible patients were HLA-DPB1*0401 positive with MAGE-A3 positive tumor specimens, and had not responded or had recurred following at least one standard first line therapy for their disease. Patients received a lymphodepleting preparative regimen, followed by adoptive transfer of purified CD4+ T cells transduced with the HLA-DPB1*0401-restricted MAGE-A3 TCR plus systemic high-dose interleukin-2 (IL-2). A cell dose-escalation was conducted, treating 1 patient at each cohort (0.01, 0.03, 0.1, up to 30 billion cells), followed by 6 patients at the highest dose level (up to 100 billion cells). Clinical trial information: NCT02111850.

Results: Fourteen patients were treated in this phase I study, including the last 6 patients at the highest dose level (78∼100 billion cells). Objective partial responses (RECIST) were observed in a patient with metastatic cervical cancer (ongoing at 11+ months), esophageal cancer (duration 3 months) and urothelial cancer (ongoing at 4+ months). High levels of IL-6 were detected in all patients’ serum samples after adoptive cell transfer. One month after the treatment, TCR-transduced T cells persisted at high levels in the peripheral blood of 6 patients who received the highest dose level, compared to patients who receive lower dose levels (0.01 ∼ 30 billion cells) (p = 0.0082). These results demonstrate the safety of administering autologous CD4+ T cells genetically-engineered to express an MHC class II-restricted anti-tumor TCR targeting MAGE-A3 and presents evidence for efficacy. We have started the phase II clinical trial to study the efficacy of this TCR therapy in different types of metastatic cancer. This clinical trial extends the reach of TCR gene therapy to patients with metastatic cancer. To our knowledge, this clinical trial represents the first genetically-modified CD4+ T cell immunotherapy against metastatic cancer.

Citation Format: Yong-Chen Lu, Linda L. Parker, Tangying Lu, Zhili Zheng, Xin Yao, Paul F. Robbins, Steven A. Feldman, Pierre van der Bruggen, Christopher A. Klebanoff, Christian S. Hinrichs, Stephanie L. Goff, Richard M. Sherry, Udai S. Kammula, James C. Yang, Steven A. Rosenberg. A phase I study of an HLA-DPB1*0401-restricted T-cell receptor targeting MAGE-A3 for patients with metastatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT003.