PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy.

Checkpoint inhibition (CPI), particularly that targeting the inhibitory coreceptor programmed cell death protein 1 (PD-1), has transformed oncology. Although CPI can derepress cancer (neo)antigen-specific αß T cells that ordinarily show PD-1-dependent exhaustion, it can also be efficacious against cancers evading αß T cell recognition. In such settings, γδ T cells have been implicated, but the functional relevance of PD-1 expression by these cells is unclear. Here we demonstrate that intratumoral TRDV1 transcripts (encoding the TCRδ chain of Vδ1+ γδ T cells) predict anti-PD-1 CPI response in patients with melanoma, particularly those harboring below average neoantigens. Moreover, using a protocol yielding substantial numbers of tissue-derived Vδ1+ cells, we show that PD-1+Vδ1+ cells display a transcriptomic program similar to, but distinct from, the canonical exhaustion program of colocated PD-1+CD8+ αß T cells. In particular, PD-1+Vδ1+ cells retained effector responses to TCR signaling that were inhibitable by PD-1 engagement and derepressed by CPI.

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

BACKGROUND: Locally 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, 4αß, 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. METHODS: We 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 1×107-1×109 T4+ T-cells, administered without prior lymphodepletion. RESULTS: Despite 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. CONCLUSIONS: These data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC.

Revitalising cancer trials post-pandemic: time for reform.

The COVID-19 pandemic posed significant risk to the health of cancer patients, compromised standard cancer care and interrupted clinical cancer trials, prompting dramatic streamlining of services. From this health crisis has emerged the opportunity to carry forward an unexpected legacy of positive reforms to clinical cancer research, where conventionally convoluted approvals processes, inefficient trial design, procedures and data gathering could benefit from the lessons in rationalisation learned during the pandemic.

Next-generation sequencing and molecular therapy.

Cancers contain a plethora of mutations, few of which are critical to maintaining a state of malignancy. With our ever-expanding understanding of the genomic complexity of cancer, potentially actionable biomarkers whose inhibition could cripple cancer growth are increasingly being elucidated. Modern cancer drug development has largely switched from cytotoxic agents to targeted therapies and immunotherapy, with noteworthy success in several cancer types including non-small-cell lung cancer (NSCLC), breast cancer and melanoma. Next-generation sequencing offers high-throughput, widescale genomic interrogation in a far more efficient and affordable manner than previous sequencing methods. This facilitates detection of potentially actionable mutations and fusions for individual patients and contributes to the identification of novel predictive and prognostic biomarkers in a population. Challenges in the technical aspects of biopsy and sequencing, interpretation, and development of targeted therapies against common genomic aberrations will need to be addressed for personalised medicine to become a reality for more patients with cancer.

A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer.

Murine tissues harbor signature γδ T cell compartments with profound yet differential impacts on carcinogenesis. Conversely, human tissue-resident γδ cells are less well defined. In the present study, we show that human lung tissues harbor a resident Vδ1 γδ T cell population. Moreover, we demonstrate that Vδ1 T cells with resident memory and effector memory phenotypes were enriched in lung tumors compared with nontumor lung tissues. Intratumoral Vδ1 T cells possessed stem-like features and were skewed toward cytolysis and helper T cell type 1 function, akin to intratumoral natural killer and CD8+ T cells considered beneficial to the patient. Indeed, ongoing remission post-surgery was significantly associated with the numbers of CD45RA-CD27- effector memory Vδ1 T cells in tumors and, most strikingly, with the numbers of CD103+ tissue-resident Vδ1 T cells in nonmalignant lung tissues. Our findings offer basic insights into human body surface immunology that collectively support integrating Vδ1 T cell biology into immunotherapeutic strategies for nonsmall cell lung cancer.