Alexander R. Anderson

IgA-Dominated Humoral Immune Responses Govern Patients' Outcome in Endometrial Cancer

Abstract Recent studies suggest that B cells could play an important role in the tumor microenvironment. However, the role of humoral responses in endometrial cancer remains insufficiently investigated. Using a cohort of 107 patients with different histological subtypes of endometrial carcinoma, we evaluated the role of coordinated humoral and cellular adaptive immune responses in endometrial cancer. Concomitant accumulation of T, B, and plasma cells at tumor beds predicted better survival. However, only B-cell markers corresponded with prolonged survival specifically in high-grade endometrioid type and serous tumors. Immune protection was associated with class-switched IgA and, to a lesser extent, IgG. Expressions of polymeric immunoglobulin receptor (pIgR) by tumor cells and its occupancy by IgA were superior predictors of outcome and correlated with defects in methyl-directed DNA mismatch repair. Mechanistically, pIgR-dependent, antigen-independent IgA occupancy drove activation of inflammatory pathways associated with IFN and TNF signaling in tumor cells, along with apoptotic and endoplasmic reticulum stress pathways, while thwarting DNA repair mechanisms. Together, these findings suggest that coordinated humoral and cellular immune responses, characterized by IgA:pIgR interactions in tumor cells, determine the progression of human endometrial cancer as well as the potential for effective immunotherapies. Significance: This study provides new insights into the crucial role of humoral immunity in human endometrial cancer, providing a rationale for designing novel immunotherapies against this prevalent malignancy. See related commentary by Osorio and Zamarin, p. 766

Study protocol for Adaptive ChemoTherapy for Ovarian cancer (ACTOv): a multicentre phase II randomised controlled trial to evaluate the efficacy of adaptive therapy (AT) with carboplatin, based on changes in CA125, in patients with relapsed platinum-sensitive high-grade serous or high-grade endometrioid ovarian cancer

Introduction Adaptive ChemoTherapy for Ovarian cancer (ACTOv) is a phase II, multicentre, randomised controlled trial, evaluating an adaptive therapy (AT) regimen with carboplatin in women with relapsed, platinum-sensitive high-grade serous or high-grade endometrioid cancer of the ovary, fallopian tube and peritoneum whose disease has progressed at least 6 months after day 1 of the last cycle of platinum-based chemotherapy. AT is a novel, evolutionarily informed approach to cancer treatment, which aims to exploit intratumoral competition between drug-sensitive and drug-resistant tumour subpopulations by modulating drug dose according to a patient’s own response to the last round of treatment. ACTOv is the first clinical trial of AT in this disease setting. Methods and analysis 80 patients will be randomised 1:1 to standard therapy (control) or AT (investigational) arms. The starting and maximum carboplatin dose in both arms is area under the curve (AUC) ×5 according to absolute nuclear medicine glomerular filtration rate. The AT regimen will modify the carboplatin dose according to changes in the serum biomarker CA125, a proxy measure of total tumour burden. Patients will receive treatment intravenously every 21 days for a maximum of 6 and 12 cycles in the control and investigational arms, respectively. The primary endpoint is modified progression-free survival (investigator-assessed using RECIST 1.1 (Response Evaluation Criteria in Solid Cancers) compared with the baseline prerandomisation scan rather than the radiological nadir), clinical progression or death from any cause. Secondary endpoints will include acceptability, deliverability, compliance, toxicity, CA125, quality of life and overall survival. ACTOv is open to National Health Service hospitals throughout the UK, recruitment is anticipated to take 36 months across 10 sites and will be managed by the Cancer Research UK and University College London Cancer Trials Centre. Ethics and dissemination The trial has been reviewed and received approval from the London—Dulwich Research Ethics Committee (REC). Results of the trial will be disseminated through publication in peer-reviewed journals. Trial registration number NCT05080556 .

To modulate or to skip: De-escalating PARP inhibitor maintenance therapy in ovarian cancer using adaptive therapy

Toxicity and emerging drug resistance pose important challenges in poly-adenosine ribose polymerase inhibitor (PARPi) maintenance therapy of ovarian cancer. We propose that adaptive therapy, which dynamically reduces treatment based on the tumor dynamics, might alleviate both issues. Utilizing in vitro time-lapse microscopy and stepwise model selection, we calibrate and validate a differential equation mathematical model, which we leverage to test different plausible adaptive treatment schedules. Our model indicates that adjusting the dosage, rather than skipping treatments, is more effective at reducing drug use while maintaining efficacy due to a delay in cell kill and a diminishing dose-response relationship. In vivo pilot experiments confirm this conclusion. Although our focus is toxicity mitigation, reducing drug use may also delay resistance. This study enhances our understanding of PARPi treatment scheduling and illustrates the first steps in developing adaptive therapies for new treatment settings. A record of this paper's transparent peer review process is included in the supplemental information.