Anti-MUC1 CAR-T cells combined with PD-1 knockout engineered T cells for patients with non-small cell lung cancer (NSCLC): A pilot study

Abstract

Background: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-related, highly chemo-radiosensitive malignancy. However, one-third of patients are considered to be incurable because of metastatic or recurrence disease. Expression of antigenic viral proteins by malignant cells constitutes a good target for immunothera-peutic strategies. Although the majority of clinical data have been obtained in the setting of EBV-related posttransplant lymphoproliferative disorders, this therapeutic approach has been more recently applied to solid tumors. Methods: We and others have implemented T-cell therapy programs for patients with NPC failing conventional treatment. The feasibility of expanding EBV-targeted cyto-toxic T lymphocytes (CTL) by stimulation with EBV-transformed lymphoblastoid cell lines (LCLs) has been demonstrated, and clinical trials were conducted, based on administration of 2 or more doses of EBV-CTLs (4-40 x 10 7 /dose), supported by in vivo rhIL-2 infusion and, in some cases, pre-treatment with lymphodepleting chemo or immunotherapy. Results: So far, more than 60 patients were treated in different centers for refractory/ relapsed advanced NPC, and about 20% objective responses, including some complete responses, were observed, with no or limited adverse events. These results are encouraging , although further improvements to the laboratory and clinical protocols are clearly necessary to increase anti-cancer activity. One approach that our center has lately pursued is to test the efficacy of CTL therapy in earlier stages of disease, in particular immediately after first line chemotherapy for relapsed disease. The clinical results of this attempt seem to improve overall survival as compared with conventional therapies, and justify a prospective trial in this specific setting. Conclusions: EBV-specific CTL therapy is safe and associated with clinical benefit in patients with refractory or metastatic NPC. Sequential combination of CTL therapy with other agents, such as checkpoint inhibitors, could yield optimal results. Background: Current standard-of-care immunotherapies target the interaction between tumor and T cells. However, frequently there are insufficient numbers of tumor-specific T cells present. Hence, these patients may benefit from adoptive cell transfer (ACT) with melanoma-specific T cells. The general conditioning and maintenance treatment for ACT consists of lymphodepleting chemotherapy with or without total body irradiation, and post-transfusion high-dose IL-2. In our hospital we replaced this rather toxic treatment scheme with low-dose interferon-alpha (IFNa). Methods: Twenty-four patients with progressive metastatic melanoma received up to three infusions with ex vivo expanded tumor infiltrating lymphocytes (TIL) every three weeks, ranging between 1-10 x 10 8 T cells per infusion. One week before the first TIL infusion patients started with daily subcutaneous IFNa injections. These injections were continued for eleven weeks as a maintenance treatment. Total blood count was measured before the start of IFNa, and before each TIL infusion. Furthermore, serum and PBMC were collected at these time-points. Twelve weeks after the first TIL infusion the patients received a radiological response evaluation. Results: The combination of IFNa and ACT is safe and well tolerated. IFNa causes a mild lymphopenia, neutropenia and leukopenia. Both responders and non-responders show a decrease in these blood counts after one week of IFNa. Strikingly, persistence of leukopenia and in particular neutropenia predicts the response to TIL therapy. Furthermore, high leukocyte/lymphocyte and platelet/lymphocyte ratios are predictive biomarkers for response to treatment. Clinical benefit was seen in 7 out of 24 (29%) patients with stable disease for an average of 36 weeks. Although nineteen patients failed