B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10 −9 ) with opposing effects between CLL (P = 1.97 × 10 −8 ) and HL (P = 3.31 × 10 −3 ). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10 −12 ) was associated with increased CLL and HL risk (P = 4.68 × 10 −12 ), and reduced MM risk (P = 1.12 × 10 −2 ), and Gly70 in HLA-DQB1 (P = 3.15 × 10 −10 ) showed opposing effects between CLL (P = 3.52 × 10 −3 ) and HL (P = 3.41 × 10 −9 ). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell

Summary Patients with haematological malignancies have a high risk of severe infection and death from SARS‐CoV‐2. In this prospective observational study, we investigated the impact of cancer type, disease activity, and treatment in 877 unvaccinated UK patients with SARS‐CoV‐2 infection and active haematological cancer. The primary end‐point was all‐cause mortality. In a multivariate analysis adjusted for age, sex and comorbidities, the highest mortality was in patients with acute leukaemia [odds ratio (OR) = 1·73, 95% confidence interval (CI) 1·1–2·72, P = 0·017] and myeloma (OR 1·3, 95% CI 0·96–1·76, P = 0·08). Having uncontrolled cancer (newly diagnosed awaiting treatment as well as relapsed or progressive disease) was associated with increased mortality risk (OR = 2·45, 95% CI 1·09–5·5, P = 0·03), as was receiving second or beyond line of treatment (OR = 1·7, 95% CI 1·08–2·67, P = 0·023). We found no association between recent cytotoxic chemotherapy or anti‐CD19/anti‐CD20 treatment and increased risk of death within the limitations of the cohort size. Therefore, disease control is an important factor predicting mortality in the context of SARS‐CoV‐2 infection alongside the possible risks of therapies such as cytotoxic treatment or anti‐CD19/anti‐CD20 treatments.

Improving the chances of curing cancer patients who have had surgery to remove metastatic sites of disease is a priority area for cancer research. Pexa-Vec (Pexastimogene Devacirepvec; JX-594, TG6006) is a principally immunotherapeutic oncolytic virus that has reached late-phase clinical trials. We report the results of a single-center, non-randomized biological endpoint study (trial registration: EudraCT number 2012-000704-15), which builds on the success of the pre-surgical intravenous (i.v.) delivery of oncolytic viruses to tumors. Nine patients with either colorectal cancer liver metastases (CRLM) or metastatic melanoma were treated with a single i.v. infusion of Pexa-Vec ahead of planned surgical resection of the metastases. Grade 3 and 4 Pexa-Vec-associated side-effects were lymphopaenia and neutropaenia. Pexa-Vec was peripherally carried in plasma and was not associated with peripheral blood mononuclear cells (PBMCs). Upon surgical resection, Pexa-Vec was found in the majority of analyzed tumors. Pexa-Vec therapy associated with interferon-α secretion, chemokine induction, and resulted in transient innate and long-lived adaptive anti-cancer immunity. In the two patients with significant and complete tumor necrosis, a reduction in the peripheral T-cell receptor diversity was observed at the time of surgery. These results support the development of pre-surgical oncolytic vaccinia virus-based therapies to stimulate anti-cancer immunity and increase the chances to cure patients with cancer.