Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study

Abstract

BackgroundLocally advanced/recurrent head and neck squamous cell carcinoma (HNSCC) is associated with significant morbidity and mortality. To target upregulated ErbB dimer expression in this cancer, we developed an autologous CD28-based chimeric antigen receptor T-cell (CAR-T) approach named T4 immunotherapy. Patient-derived T-cells are engineered by retroviral transduction to coexpress a panErbB-specific CAR called T1E28ζ and an IL-4-responsive chimeric cytokine receptor, 4αβ, which allows IL-4-mediated enrichment of transduced cells during manufacture. These cells elicit preclinical antitumor activity against HNSCC and other carcinomas. In this trial, we used intratumoral delivery to mitigate significant clinical risk of on-target off-tumor toxicity owing to low-level ErbB expression in healthy tissues.MethodsWe undertook a phase 1 dose-escalation 3+3 trial of intratumoral T4 immunotherapy in HNSCC (NCT01818323). CAR T-cell batches were manufactured from 40 to 130 mL of whole blood using a 2-week semiclosed process. A single CAR T-cell treatment, formulated as a fresh product in 1–4 mL of medium, was injected into one or more target lesions. Dose of CAR T-cells was escalated in 5 cohorts from 1×107−1×109T4+T-cells, administered without prior lymphodepletion.ResultsDespite baseline lymphopenia in most enrolled subjects, the target cell dose was successfully manufactured in all cases, yielding up to 7.5 billion T-cells (67.5±11.8% transduced), without any batch failures. Treatment-related adverse events were all grade 2 or less, with no dose-limiting toxicities (Common Terminology Criteria for Adverse Events V.4.0). Frequent treatment-related adverse events were tumor swelling, pain, pyrexias, chills, and fatigue. There was no evidence of leakage of T4+T-cells into the circulation following intratumoral delivery, and injection of radiolabeled cells demonstrated intratumoral persistence. Despite rapid progression at trial entry, stabilization of disease (Response Evaluation Criteria in Solid Tumors V.1.1) was observed in 9 of 15 subjects (60%) at 6 weeks post-CAR T-cell administration. Subsequent treatment with pembrolizumab and T-VEC oncolytic virus achieved a rapid complete clinical response in one subject, which was durable for over 3 years. Median overall survival was greater than for historical controls. Disease stabilization was associated with the administration of an immunophenotypically fitter, less exhausted, T4 CAR T-cell product.ConclusionsThese data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC.

The use of T-cells with chimeric antigen receptor (CAR-T) in combination with chemotherapy and radiotherapy for the treatment of solid tumors

“…В ряде исследований показано, что карбоплатин способен усиливать эффект CAR-T-клеток, нацеленных на рецептор Erb-B. Это приводит к более быстрой деградации опухолевых клеток [70][71][72]. Также ХТ способна влиять на микроокружение опухоли, в частности снижать ее иммуносупрессивные свойства.…”

Immunotherapeutic Agents for Intratumoral Immunotherapy

“…A case reported that intratumoral adoptive immunotherapy with TILs in patients with melanoma, in combination with subcutaneous infusion of IL-2 and a single intratumoral injection of a low dose of IFNα, led to consistent tumor regression [63]. With the enormous clinical successes of CAR-T cells in B-cell leukemias and lymphomas, but not for solid tumors with the intravenous route, direct injection of CAR-T cells with different genetic modifications into tumors could improve the efficacy in solid malignancies for this class of therapies [64]. Repeated intratumoral injections of CAR-modified T cells specific to erbB-2 accumulated cells at tumor sites have eliminated tumor cells as well as prevented relapse in a mouse spontaneous mammary tumor model due to overexpression of the human erbB-2 transgene [120].…”

“…Repeated intratumoral injections of CAR-modified T cells specific to erbB-2 accumulated cells at tumor sites have eliminated tumor cells as well as prevented relapse in a mouse spontaneous mammary tumor model due to overexpression of the human erbB-2 transgene [120]. A phase I dose-escalation study was conducted for intratumoral CAR-T cell therapy, in which intratumoral ErbB-targeted T4 CAR-T cells were tested in patients with squamous cell carcinoma of the head and neck following locoregional recurrence, and the safety of intratumoral injection of T4 CAR-T immunotherapy was shown [64]. In a phase 0 clinical trial, intratumoral administration of mRNA-transfected c-Met-CAR-T cells was applied on patients with metastatic breast cancer with accessible cutaneous or lymph node metastases; it was reported that mRNA c-Met-CAR T cell injections were well tolerated and caused tumor necrosis which was surrounded by macrophages [65].…”

The role of CD4+ CAR T cells in cancer immunotherapy

“…Risk of toxicity and enhanced delivery to the TME may be further reduced by chemokine receptor armouring, thereby directing CAR T cells more efficiently to tumours that produce cognate chemokines, whilst avoiding low antigen expressing healthy cells ( 7 , 8 ). Alternatively, where appropriate, CAR T cells can be injected intratumourally, although penetration within target lesions remains sub-optimal ( 9 ).…”

“…In the colorectal study, a CD4 + T cell population with a strongly cytotoxic gene signature was once again identified. In a phase 1 dose escalation trial undertaken in our centre to evaluate intratumoural pan erythroblastic leukaemia viral oncogene homologue (ErbB)-specific CAR T cells in patients with relapsed refractory head and neck squamous cell carcinoma, we found that the administration of CD4 + T cell rich CAR product was correlated with superior outcome ( 9 ). However, although CD4 + CAR T cells drive potent anti-tumour efficacy, evidence also suggests that these cells are the main drivers of associated adverse events, such as CRS ( 32 , 44 ).…”