The Christie School of Oncology: Christie Research Publications Repository
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Immunometabolic gatekeeping: reconciling peto's & the t-cell infiltration prognostic paradox
No full textClassical models of cancer focus on tumour-intrinsic genetic aberrations and immune dynamics and often overlook how the metabolic environment of healthy tissues shapes tumour development and immune efficacy. Here, we propose that tissue-intrinsic metabolic intensity and waste-handling capacity act as an upstream gatekeeper of anti-tumour immunity, determining whether immune infiltration translates into effective immune function and safeguards the tissue from tumourigenesis. Across human cancers, tumours arising in high-metabolism tissues - like kidney, brain, and eye - tend to show high T cell infiltration but poor prognosis, suggesting pre-existing metabolic environments prior to malignant transformation may undermine immune function. This pattern is mirrored across species: large mammals with lower mass-specific metabolic rates (e.g., elephants, whales) accumulate fewer metabolic byproducts and show lower cancer incidence (Peto's paradox), while long-lived small mammals like bats and naked mole-rats resist tumourigenesis via suppressed glycolysis or altered hypoxia responses leading to lower metabolic rates and/or byproduct accumulation. Through integrative synthesis spanning human single-cell expression data and cross-species comparisons, we outline a framework of"immunometabolic gatekeeping," where tissues with high metabolic rate and poor waste clearance foster immune-exhausting niches even before transformation. This unifying framework reconciles multiple paradoxes in cancer biology: Peto's paradox, T cell infiltration non-prognosticity, tissue tropisms, sex-based inequalities, and size-based tipping points (e.g., the 3 cm rule in ccRCC), and suggests new principles for identifying high-risk patients and metabolic-immune combination strategies for prevention and treatment. By shifting focus from tumour-intrinsic mutations to host-tissue metabolism, this work offers a novel, integrative lens on cancer vulnerability and immune failure
Novel pembrolizumab-based treatments as first-line therapy in advanced clear cell renal cell carcinoma: Substudy 03A of the open-label, umbrella platform, phase I/II KEYMAKER-U03 trial
No full textBACKGROUND: First-line triplet therapy may expand clinical benefit for advanced clear cell renal cell carcinoma (ccRCC). The phase Ib/II KEYMAKER-U03 Substudy 03A (NCT04626479) investigated novel pembrolizumab (pembro)-based regimens in this setting. METHODS: Participants with advanced ccRCC and no prior systemic therapy were randomized 2:1 to quavonlimab (qmab)/pembro plus lenvatinib (lenva), favezelimab (fave)/pembro plus lenva, pembro plus lenva plus belzutifan (bel), and vibostolimab (vibo)/pembro plus bel or a concurrent reference treatment (pembro plus lenva). A safety lead-in of ∼10 participants occurred for all investigative treatments before randomization. Primary endpoints were objective response rate (ORR) per RECIST v1.1 by blinded independent central review in all randomized participants (excluding safety lead-in), and safety in all treated participants. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). RESULTS: As of March 31, 2025, 393 participants were enrolled. Median follow-up for randomized participants across the 5 cohorts ranged between 16 and 39 months. ORR (95% CI) was 80.6% (68.6-89.6) with pembro plus lenva, 71.3% (60.0-80.8) with qmab/pembro plus lenva, 62.7% (48.1-75.9) with fave/pembro plus lenva, 77.5% (66.8-86.1) with pembro plus lenva plus bel, and 42.5% (31.5-54.1) with vibo/pembro plus bel. Median PFS (95% CI) in months was 26.3 (15.3-39.8) with pembro plus lenva, 18.0 (11.6-34.3) with qmab/pembro plus lenva, 26.0 (8.2-31.8) with fave/pembro plus lenva, 31.8 (26.3-NR) with pembro plus lenva plus bel, and 15.2 (12.4-NR) with vibo/pembro plus bel. Median OS was not reached in any arm. Grade ≥3 treatment-related adverse events occurred in 71.0% (44/62) of participants treated with pembro plus lenva, 73.3% (66/90) with qmab/pembro plus lenva, 86.9% (53/61) with fave/pembro plus lenva, 70.0% (63/90) with pembro plus lenva plus bel, and 68.9% (62/90) with vibo/pembro plus bel. CONCLUSIONS: Observed efficacy and safety of pembro plus lenva were confirmatory of prior observations for this combination. ORR was similar to reference for pembro plus lenva plus bel and qmab/pembro plus lenva, but not the other investigative arms. Further investigation of pembro plus lenva plus bel and qmab/pembro plus lenva versus pembro plus lenva is ongoing in the phase 3 LITESPARK-012 study
Radiotherapy commissioning and tariff-how can we deliver advanced, innovative, and personalised radiotherapy?
No full textRadiotherapy practices have changed significantly over recent decades with the introduction of increasingly personalised approaches to preparation and treatment and the use of a wider range of imaging technology, treatment techniques and software such as Artificial Intelligence (AI). The lack of development of the radiotherapy tariff, which remunerates services for radiotherapy delivery, has contributed to poor adoption rates and inequitable access for patients to new advanced treatment technologies and software across England. The radiotherapy tariff has a potential to be a lever to drive innovation across the system, if it is routinely updated to respond to latest clinical consensus. The commissioning of radiotherapy services is being transferred from NHS England to Integrated Care Boards (ICBs), in their emerging role as 'strategic commissioners'. Along with wider reform to funding mechanisms set out in the 10 Year Health Plan, this presents an opportunity to reshape the commissioning and tariff structures for radiotherapy services to better reflect contemporary radiotherapy practice. This paper explores the limitations of current funding arrangements for radiotherapy. It proposes recommendations to ensure that providers are supported to deliver more productive, innovative and value-based radiotherapy
External reproduction of a causal estimation of the individual and cohort benefit of sequential vs concurrent chemoradiotherapy in SIII NSCLC patients
No full textProphylactic cranial irradiation for patients with SCLC-a new perspective in the immunotherapy era
No full textProphylactic cranial irradiation (PCI) has long been used for SCLC to reduce the risk of brain metastases and potentially improve overall survival. Nevertheless, recent immunotherapy trials have provided limited data on its impact, as few patients were treated with PCI. The ADRIATIC trial reported improved outcomes with consolidation immunotherapy in limited-stage SCLC, and PCI was a stratification factor. Notably, patients receiving PCI in both arms had better outcomes than those who did not. Ongoing studies, such as EORTC-1901 PRIMALung (NCT04790253) and SWOG 1827-MAVERICK (NCT04155034), are further investigating PCI's role in the era of immunotherapy, highlighting its potential importance in evolving treatment strategies. (c) 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies
First-line therapy (1L) of cisplatin/gemcitabine (CisGem) with pembrolizumab (pembro) in patients with advanced biliary tract cancer (aBTC): open-label, single-arm phase II EORTC-1607-GITCG/ABC-09 intergroup study with translational research (TR)
No full textA matter of survival-patients' and carers' perspectives on the decision to undergo pelvic exenteration surgery for locally advanced and recurrent rectal cancer
No full textAimPelvic exenteration is the only potentially curative treatment for patients with locally advanced or recurrent rectal cancer. This study aimed to investigate how patients decide to undergo such radical surgery.MethodThis qualitative study employed an exploratory interpretive design informed by hermeneutic philosophy. During semi-structured interviews, individuals who had undergone pelvic exenteration at a specialised centre and their carers were asked to reflect on the decision-making process around surgery.ResultsThirty-eight interviews were conducted with 39 participants (34 patients and five carers). Four themes were identified. There really wasn't a choice-participants indicated that long-term survival was their absolute priority, with many feeling that there was no alternative. Only one participant expressed decision regret due to the consequences of surgery. Grappling with the magnitude of surgery-despite extensive preoperative education and counselling, the enormity of the surgery and recovery experience was incomprehensible to participants until they were 'in it', with many surprised by a slow and protracted recovery. A spectrum of psychological states and support needs-participants reflected on their psychological state prior to surgery, identifying family or professional pre-surgery counselling as sources of support. Understanding life after surgery-although most participants were willing to accept anything in order to survive, many identified the impact on bodily functions, body image and overall quality of life as important.ConclusionsLong-term survival was the principal factor influencing the decision to undergo pelvic exenteration. Individualised preoperative counselling may improve patient preparedness for the consequences of surgery
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No full textBoosting Dendritic Cell Function in Cancer
No full textInstruction of T cell immunity is a key function of sentinel leukocytes called dendritic cells (DC). Several studies in mice and humans have demonstrated a key role for DCs in promoting T cell responses to cancer and augmenting the efficacy of T cell-based immunotherapies. Like other innate immune cells, DCs express a wide repertoire of receptors endowing them with the ability to detect microbial presence and tissue damage. These functions contribute to cancer immunity and have been previously linked to the induction of anti-tumour CD8(+) T cells and enhanced responses to immune checkpoint blockade (ICB) therapy. Here, I review some of the principles of DC biology, highlighting their functional characteristics that dictate T cell responses to cancer and how these can be harnessed in the design of novel immunotherapies