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.

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.

Cancers contain a plethora of mutations, few of which are critical to maintaining a state of malignancy. With our everexpanding 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 nonsmall-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. Genomic alterations in cancersCancer-causing genomic alterations either enhance the function of progrowth oncogenes, such as BRAF, or abrogate that of tumour suppressor genes, such as TP53. Inheritance of these mutations in the germline accounts for a minority of cancers; more commonly, they arise sporadically in somatic cells. The minimum number of such mutations required to facilitate carcinogenesis is estimated between two and eight, 4 but most cancers contain thousands

9018 Background: VS-6766 is a small molecule RAF/MEK clamp that results in the reduction of p-MEK and p-ERK. Preclinical data show synergy of VS-6766 with the mTOR inhibitor everolimus across a panel of KRAS mutated (mt) NSCLC cell lines. This clinical trial evaluated the safety and efficacy of a novel intermittent regimen of VS-6766 and everolimus with an expansion in KRAS mt NSCLC (NCT02407509). Methods: The trial used a 3+3 dose escalation design with an intermittent once a week schedule A, and if tolerated, twice a week schedule B (Mon-Thu or Tue-Fri) for both drugs on a 3 weeks on/1 week off, 28 day cycle. Patients with RAS or RAF mt cancers were eligible for the dose escalation cohort, and 20 patients with KRAS mt NSCLC will be treated in the dose expansion cohort. Toxicity was evaluated by NCI CTC V4 and efficacy was evaluated using RECIST 1.1. Results: A total of 28 patients have been treated; median age 60 yrs (range 36-78), and median lines of previous treatment 3 (range 0-7). Sixteen patients have been treated in the dose escalation (3 in schedule A and 13 in the schedule B). The doses of 4 mg of VS-6766 and 5 mg everolimus (once weekly) were tolerated with no dose limiting toxicities (DLTs) and the dose intensity escalated to schedule B (twice weekly). At 4 mg VS-6766 twice weekly, DLTs were observed in two out of six patients and included grade 4 CPK elevation and grade 3 rash. Thus, the dose in schedule B (twice weekly) was de-escalated to 3.2 mg VS-6766 and the dose of everolimus was kept at 5 mg. No DLTs were reported in 6 patients and thus this was declared as the recommended phase 2 dose (RP2D). At the RP2D, the grade 3-4 drug related AE were rash (18%) and pruritus (7%). In the dose escalation cohorts, 3 partial responses (PRs) were reported (2 KRAS G12D low grade serous ovarian cancer and 1 NRAS Q61K mt thyroid cancer). In the KRAS mt NSCLC expansion cohort, 10 patients are evaluable for efficacy and 2 confirmed responses were reported ( KRAS mutations G12V and G13A) with an objective response rate (ORR) 20% to date. The disease control rate (PR + SD) at the first scheduled evaluation was 90%. The median progression free survival (PFS) in the KRAS mt NSCLC cohort is 6.35 months (95% CI 3.52 – not reached). Updated ORR and PFS data will be presented. Conclusions: A tolerable intermittent dosing schedule targeting both the MAPK and PI3K pathways has been established. The combination of VS-6766 with everolimus has shown activity in patients with a variety of KRAS mutation variants including responses in KRAS mt NSCLC.

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