Sophie Papa, MD
Beyond hematologic malignancies, chimeric antigen receptor (CAR) T-cell therapy could have potential in solid tumors, such as head and neck cancer, according to early results of a clinical trial presented at the 2017 AACR Annual Meeting.
In the dose-escalation phase I study, patients with head and neck squamous cell carcinoma were treated with T4 immunotherapy, which are T cells that are retroviral transduced to co-express T1E28ζ, a CAR coupling an ErbB ligand derived from EGF and TGFα to a fused CD28+CD3ζ endodomain, and 4αβ, a chimeric cytokine receptor containing the IL-4Rα ectodomain coupled to the IL-2Rβ endodomain.
While 90% of patients were lymphopenic, the T4 therapy was generated from a 130-mL blood draw in a closed manufacturing process. The authors noted, in the study, that batches contained up to 7.5 x 109
cells, of which 63.8 +/- 12.1% were T4+. This comprised a variable mixture of central and effector memory CD4-positive and CD8-positive T cells. Cohorts of 1, 3, and 10 x 107 T4+ T cells were treated.
Results showed that the disease control rate was 44%, and all 3 patients in cohort 3 achieved stable disease. Regarding safety, treatment-related adverse events (AEs) were found to be grade 2 or lower, with no dose-limiting toxicities observed. The most commonly experienced AEs were tumor swelling or pain and fatigue.
In an interview with OncLive
during the meeting, lead study author Sophie Papa, MD, medical oncologist, Clinical Academic Group, Department of Research Oncology, King’s College London, discusses the early-phase results and the logic behind studying CAR T-cell therapy in solid tumors, such as head and neck cancer.
OncLive: Could you please provide an overview of the study being presented at this year’s meeting?
CAR T-cell therapy has really begun to become the standard of care in hematologic cancers that express CD19, and has made a huge impact on survival for patients with resistant, heavily pretreated cancers in that setting. What we are trying to do is use a CAR T-cell approach to treat a very different type of malignancy, head and neck squamous cell carcinoma.
Solid tumors pose [several] different challenges to CAR T-cell therapy. Some of the key ones we are trying to address with our protocol are, first and foremost, the fact that in the CD19 CAR T cells we are seeing, resistance is occurring, and the tumors are losing expression of the target CD19. Our approach uses a receptor that is based on the ligand that is able to interact with more than 1 receptor. Therefore, we are offering an approach that is hopefully going to overcome a degree of resistance in the tumor.
We are also trying to treat the patient population that carries a very heavy burden of comorbidities. The patients who suffer from head and neck cancer traditionally are older, frail, and have other comorbidities affecting their health. Using some of these approaches that have been instrumental in the success of CD19 CAR T-cell therapies opens up the risk of toxicity with cytokine release syndrome, neurotoxicity, etc, which is going to be harder to undertake in this patient population.
With the T4 trial, T cells are administered intratumorally rather than intravenously to try to target the activity where it’s needed in the locoregional disease, reduce the risk of the T cells getting into the circulation, and cause toxicity on target—but off tumor. We are not lymphodepleting the patients to try and reduce the toxicities associated with this therapy.