Objective: To determine the impact of Human Papilloma Virus (HPV) oropharyngeal cancer (OPC) status on the prediction of head and neck squamous cell cancer (HNSCC) chemoradiotherapy (CRT) outcomes with pre-treatment quantitative diffusion-weighted magnetic resonance imaging (DW-MRI). Methods: Following ethical approval, 65 participants (53 male, age 59.9 ± 7.86) underwent pre-treatment DW-MRI in this prospective cohort observational study. There were 46 HPV OPC and 19 other HNSCC cases with stage III/IV HNSCC. Regions of interest (ROIs) (volume, largest area, core) at the primary tumour (n = 57) and largest pathological node (n = 59) were placed to analyse ADCmean and ADCmin. Unpaired t-test or Mann-Whitney test evaluated the impact of HPV OPC status and clinical parameters on their prediction of post-CRT 2 year loco-regional and disease-free survival (LRFS and DFS). Multivariate logistic regression compared significant variables with 2 year outcomes. Results: On univariate analysis of all participants, the primary tumour area ADCmean was predictive of 2 year LRFS (p = 0.04). However, only the HPV OPC diagnosis (LFRS p = 0.03; DFS p = 0.02) predicted outcomes on multivariate analysis. None of the pre-treatment ADC values were predictive of 2 year DFS in the HPV OPC subgroup (p = 0.21–0.68). Amongst participants without 2 year disease-free survival, HPV-OPC was found to have much lower primary tumour ADCmean values than other HNSCC. Conclusion: Knowledge of HPV OPC status is required in order to determine the impact of the pre-treatment ADC values on post-CRT outcomes in HNSCC. Advances in knowledge: Pre-treatment ADCmean and ADCmin values acquired using different ROI methods are not predictive of 2 year survival outcomes in HPV OPC.

Striking progress has been achieved in CD19+ hematologic malignancies using chimeric antigen receptor (CAR) T-cells following lymphodepletion. Nonetheless, toxicity remains significant, due to cytokine release syndrome (CRS) and neurologic dysfunction. The frequent emergence of resistance due to antigen loss provides a strong rationale for engagement of multiple targets. Solid tumors impose additional challenges. Foremost, a paucity of targets that are tumor-specific, or restricted to dispensable tissues. Moreover, active CAR T-cells need to home to, penetrate and persist within profoundly immunosuppressive tumors. Cognizant of these obstacles, we designed T4 immunotherapy. T4+ T-cells are retroviral transduced to co-express (i) T1E28ζ, a CAR coupling a promiscuous ErbB ligand derived from EGF and TGFα to a fused CD28+CD3ζ endodomain; and (ii) 4αβ, a chimeric cytokine receptor containing the IL-4Rα ectodomain coupled to the IL-2Rβ endodomain. T1E28ζ engages 8/9 possible ErbB dimers, providing broad anti-tumor activity while minimizing risk of antigen escape. 4αβ enables IL-4-driven selective enrichment and expansion of CAR T-cells during manufacture. Pre-clinical data demonstrate potent anti-tumor activity in head and neck squamous cell carcinoma (HNSCC), mesothelioma, ovarian and breast cancer. However, risk of on-target off-tumor toxicity is significant, due to low-level ErbB expression in normal tissues. Indeed, CRS can be modeled when human T4+ T-cells are administered to the peritoneal cavity of SCID Beige mice. To de-risk T4 immunotherapy in man, a dose-escalation intra-tumoral Phase I trial was commenced, without lymphodepletion. HNSCC was selected due to the unmet need presented by locally advanced or recurrent disease. Ninety percent of patients were lymphopenic yet T4 immunotherapy was successfully generated from a 130mL blood draw, in a closed manufacturing process. Batches contained up to 7.5 x 109 cells, of which 63.8+ 12.1% were T4+, comprising a variable mixture of central and effector memory CD4+ and CD8+ T-cells. Cohorts of 1, 3 and 10 x 107 T4+ T-cells were treated. Patient 5 died of advanced HNSCC, prior to treatment. Intra-tumoral 1-2mL injections of T4 immunotherapy were administered as a single dose. Treatment-related AEs were < grade 2, with no dose-limiting toxicities (CTCAE v4.0). Common AEs were tumor swelling/ pain and fatigue. All patients experienced a self-limited rise in CRP. Grade 1 chills occurred in cohort 3 within 24h. Circulating T4+ T-cells were not seen. Disease control rate was 44% with all three patients in cohort 3 achieving stable disease (RECIST 1.1 at 6 weeks). These data demonstrate the safe intra-tumoral administration of T4-immunotherapy in patients with advanced HNSCC, with disease control observed at the highest dose tested. Further dose escalation and combination with immune-modulating agents is warranted. Citation Format: Sophie Papa, Antonella Adami, Michael Metoudi, Daniela Achkova, May van Schalkwyk, Ana Parente Pereira, Leticia Bosshard-Carter, Lynsey Whilding, Sjoukje van der Stegen, David M. Davies, Teresa Guerrero-Urbano, Jean Pierre Jeannon, James Spicer, John Maher. T4 immunotherapy of head and neck squamous cell carcinoma using pan-ErbB targeted CAR T-cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT118. doi:10.1158/1538-7445.AM2017-CT118

Objectives To evaluate the ability of post-chemo-radiotherapy (CRT) diffusion-weighted-MRI apparent diffusion coefficient (ADCmean) and 18F-FDG PET maximum standardized uptake value (SUVmax) to predict disease-free survival (DFS) in head and neck squamous cell carcinoma (HNSCC), and to determine whether this ability is influenced by human papillomavirus oropharyngeal cancer (HPV-OPC) status. Methods This prospective cohort observational study included 65 participants (53 male, mean ± SD age 59.9 ± 7.9 years, 46 HPV-OPC) with stage III or IV HNSCC. Primary tumour and nodal ADCmean (pre-treatment, 6- and 12-weeks post-CRT) and SUVmax (12-weeks post-CRT) were measured. Variables were compared with 2-year DFS (independent t-test/Mann–Whitney test) and overall DFS (Cox regression), before and after accounting for HPV-OPC status. Variables were also compared between HPV-OPC and other HNSCC subgroups after stratifying for DFS. Results Absolute post-CRT ADCmean values predicted 2-year DFS and overall DFS for all participants (p = 0.03/0.03, 6-week node; p = 0.02/0.03 12-week primary tumour) but not in the HPV-OPC subgroup. In participants with DFS, percentage interval changes in primary tumour ADCmean at 6- and 12-weeks were higher in HPV-OPC than other HNSCC (p = 0.01, 6 weeks; p = 0.005, 12 weeks). The 12-week post-CRT SUVmax did not predict DFS. Conclusion Absolute post-CRT ADCmean values predicted DFS in HNSCC but not in the HPV-OPC subgroup. Amongst participants with DFS, post-CRT percentage interval changes in primary tumour ADCmean were significantly higher in HPV-OPC than in other HNSCC. Knowledge of HPV-OPC status is crucial to the clinical utilisation of post-CRT DWI-MRI for the prediction of outcomes.

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Background: The provision of cancer services has been strongly impacted by the outbreak of SARS-CoV-2. Our Cancer Centre in South-East London treats about 8,800 patients annually (incl. 4,500 new diagnoses) and is one of the largest Comprehensive Cancer Centres in the UK. The first COVID-19 positive cancer patient was reported on 29 Feb 2020. Whilst we are dealing with the second wave of COVID-19, it is important to further evaluate safety of cancer treatments whilst balancing risks of COVID-19 infection and complications. Methods: Using descriptive statistics, we report on the patient/tumour characteristics as well as short-term clinical outcomes of those patients undergoing radical treatment (i.e. systemic anticancer treatment (SACT), surgery, or radiotherapy (RT)) for their cancer during the first wave as to help establish the clinical guidelines for the management of cancer patients in a SARS-CoV-2 epidemic. Results: Between March-July 2020, 1,553 patients underwent surgery, 1,125 received SACT, and 814 had RT. Compared to the same period in 2019, there was a decrease of 28% for surgery, 15% for SACT, and 10% for radiotherapy. Whilst surgery was performed on more male patients (58%), more women received SACT (75%) and RT (58%). The age distribution was similar between treatment arms, with the majority of patients aged 50 to 80 years. The most common tumour types were breast (21%), thoracic (20%), and urological (29%) for surgical treatment; breast (49%), gastrointestinal (18%), and gynaecological (10%) for SACT; and breast (40%), urology (25%), and head & neck (11%) for RT. Within SACT, 36% received combination therapy, 35% received systemic chemotherapy, 23% targeted therapy, 5% immunotherapy, and 2% biological therapy. In terms of oncological outcomes, outcomes were similar to pre-COVID-19 times; with 6 deaths at 30 days (<1%) for surgical patients and 36 readmissions (2%), 10 deaths (<1%) for SACT patients, and 52% of RT delivered with radical intent (which was the same in 2019). The COVID-19 infection rates for our patients were very low: 12 patients were positive pre-surgery (1%), 7 post-surgery (<1%), 17 SACT patients (2%) and 3 RT patients (<1%). No COVID-19 related deaths were registered for the surgical, SACT and RT patients. Conclusion: Whilst there was a decline in overall radical treatment, likely due to a delay in cancer diagnoses, those who did undergo their treatment were treated in a safe COVID-19 managed environment. Our findings highlight that cancer patients should have the confidence to attend hospitals and be reassured of the safety measurements taken. Citation Format: Beth Russell, Victoria Harris, Harvey Dickinson, Charlotte Moss, Graham Roberts, Kate Haire, Eirini Tsotra, Harris Gousis, Debra Josephs, Deborah Enting, Ailsa Sita-Lumsden, Jose Roca, Vasilliki Michalaera, Mary Lei, Angela Swampillai, Eleanor Sawyer, Daniel Smith, Irene De Francesco, Teresa Guerrero-Urbano, Mieke Van Hemelrijck, Saoirse Dolly, Guy's Cancer Real World Evidence. Radical cancer treatment is safe during COVID-19: The experience of a large London-based Comprehensive Cancer Centre [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P18.