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Live-attenuated Listeria monocytogenes has shown encouraging potential as an immunotherapy platform in preclinical and clinical settings. However, additional safety measures will enable application across malignant and infectious diseases. Here, we describe a new vaccine platform, termed Lm-RIID (L. monocytogenes recombinase-induced intracellular death), that induces the deletion of genes required for bacterial viability yet maintains potent T cell responses to encoded antigens. Lm-RIID grows normally in broth but commits suicide inside host cells by inducing Cre recombinase and deleting essential genes flanked by loxP sites, resulting in a self-limiting infection even in immunocompromised mice. Lm-RIID vaccination of mice induces potent CD8+ T cells and protects against virulent challenges, similar to live L. monocytogenes vaccines. When combined with α-PD-1, Lm-RIID is as effective as live-attenuated L. monocytogenes in a therapeutic tumor model. This impressive efficacy, together with the increased clearance rate, makes Lm-RIID ideal for prophylactic immunization against diseases that require T cells for protection.

Background This study examined real-world patients with locally advanced or metastatic urothelial carcinoma considered ineligible for platinum-containing chemotherapy in the first-line setting. Methods This retrospective observational study used data from a nationwide (United States) de-identified patient-level electronic health record–derived database. Eligible adults (aged 18 years and older) had a locally advanced or metastatic urothelial carcinoma diagnosis on or after January 1, 2016, and initiated first-line systemic treatment at least 90 days before December 31, 2021. Platinum ineligibility was defined as Eastern Cooperative Oncology Group performance status of at least 3, creatinine clearance less than 30 mL/min, or Eastern Cooperative Oncology Group performance status of 2 and creatinine clearance of less than 45 mL/min. Overall survival and real-world progression-free survival (PFS) were summarized using the Kaplan–Meier method. Results The overall population comprised 4270 patients; 477 (11%) were considered platinum ineligible, 262 (55%) received a first-line programmed cell death 1 or programmed cell death ligand 1 immune checkpoint inhibitor, and 118 (25%) received platinum-based chemotherapy. A total of 2335 (55%) patients were platinum eligible; 677 (29%) received a first-line programmed cell death 1 or programmed cell death ligand 1 inhibitor, and 1229 (53%) received platinum-based chemotherapy. Median overall survival was 13.3 months (95% confidence interval [CI] = 12.4 to 14.8 months) in platinum-eligible and 5.1 months (95% CI = 4.2 to 6.4 months) in platinum-ineligible patients. Median PFS was shorter in platinum-ineligible (3.4 months; 95% CI = 2.9 to 4.0 months) vs platinum-eligible patients (5.9 months; 95% CI = 5.5 to 6.2 months) overall and when stratified by first-line therapy type. Conclusion This real-world study has shown for the first time the treatment patterns and outcomes in newly diagnosed patients with locally advanced or metastatic urothelial carcinoma ineligible for platinum-based chemotherapy. These findings provide quantitative benchmarks for platinum ineligibility in the first-line advanced or metastatic urothelial carcinoma setting and highlight the need for novel therapy options. [ABSTRACT FROM AUTHOR]

IL-15 has potential as an immunotherapeutic agent for cancer treatment because it is a critical factor for the proliferation and activation of NK and CD8+ T cells. However, monotherapy of patients with malignancy with IL-15 that has been initiated may not be optimal, because of the limited expression of the private receptor, IL-15Rα. We demonstrated greater CD8 T cell-mediated therapeutic efficacy using a combination regimen of murine IL-15 administered with an agonistic anti-CD40 Ab (FGK4.5) that led to increased IL-15Rα expression on dendritic cells (DCs), as well as other cell types, in a syngeneic established TRAMP-C2 tumor model. Seventy to one hundred percent of TRAMP-C2 tumor-bearing wild-type C57BL/6 mice in the combination group manifested sustained remissions, whereas only 0-30% in the anti-CD40-alone group and none in the murine IL-15-alone group became tumor free (p < 0.001). However, the combination regimen showed less efficacy in TRAMP-C2 tumor-bearing IL-15Rα-/- mice than in wild-type mice. The combination regimen significantly increased the numbers of TRAMP-C2 tumor-specific SPAS-1/SNC9-H8 tetramer+CD8+ T cells, which were associated with the protection from tumor development on rechallenge with TRAMP-C2 tumor cells. Using an in vitro cytolytic assay that involved NK cells primed by wild-type or IL-15Rα-/- bone marrow-derived DCs, we demonstrated that the expression of IL-15Rα by DCs appeared to be required for optimal IL-15-induced NK priming and killing. These findings support the view that anti-CD40-mediated augmented IL-15Rα expression was critical in IL-15-associated sustained remissions observed in TRAMP-C2 tumor-bearing mice receiving combination therapy. [ABSTRACT FROM AUTHOR]

Background: This study examined real-world patients with locally advanced or metastatic urothelial carcinoma considered ineligible for platinum-containing chemotherapy in the first-line setting., Methods: This retrospective observational study used data from a nationwide (United States) de-identified patient-level electronic health record-derived database. Eligible adults (aged 18 years and older) had a locally advanced or metastatic urothelial carcinoma diagnosis on or after January 1, 2016, and initiated first-line systemic treatment at least 90 days before December 31, 2021. Platinum ineligibility was defined as Eastern Cooperative Oncology Group performance status of at least 3, creatinine clearance less than 30 mL/min, or Eastern Cooperative Oncology Group performance status of 2 and creatinine clearance of less than 45 mL/min. Overall survival and real-world progression-free survival (PFS) were summarized using the Kaplan-Meier method., Results: The overall population comprised 4270 patients; 477 (11%) were considered platinum ineligible, 262 (55%) received a first-line programmed cell death 1 or programmed cell death ligand 1 immune checkpoint inhibitor, and 118 (25%) received platinum-based chemotherapy. A total of 2335 (55%) patients were platinum eligible; 677 (29%) received a first-line programmed cell death 1 or programmed cell death ligand 1 inhibitor, and 1229 (53%) received platinum-based chemotherapy. Median overall survival was 13.3 months (95% confidence interval [CI] = 12.4 to 14.8 months) in platinum-eligible and 5.1 months (95% CI = 4.2 to 6.4 months) in platinum-ineligible patients. Median PFS was shorter in platinum-ineligible (3.4 months; 95% CI = 2.9 to 4.0 months) vs platinum-eligible patients (5.9 months; 95% CI = 5.5 to 6.2 months) overall and when stratified by first-line therapy type., Conclusion: This real-world study has shown for the first time the treatment patterns and outcomes in newly diagnosed patients with locally advanced or metastatic urothelial carcinoma ineligible for platinum-based chemotherapy. These findings provide quantitative benchmarks for platinum ineligibility in the first-line advanced or metastatic urothelial carcinoma setting and highlight the need for novel therapy options., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming therapeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder cancers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8 + cytotoxic T lymphocyte (CTL) responses compared with anti-PD-L1 alone. Circulating CTLs from cancer patients with high plasma IL-6 display a repressed functional profile based on single-cell RNA sequencing, and IL-6-STAT3 signaling inhibits classical cytotoxic differentiation of CTLs in vitro. In tumor-bearing mice, CTL-specific IL6R deficiency is sufficient to improve anti-PD-L1 activity. Thus, based on both clinical and experimental evidence, agents targeting IL-6 signaling are plausible partners for combination with ICIs in cancer patients., Competing Interests: Declaration of interests M.A.H., K.Y., L.W., J.E.K., L.L., Y.L., V.G., C.L., D.R., C.O., S.M., S.K., Y.J.C., J.P., Y.S., Z.M., B.B., E.J.F., N.L., H.K., J.Z., M.F., P.W., M.W., I.M., S.J.T., M.M., S.M., L.M., and N.R.W. are employees of Genentech, Inc. M.A.H., K.Y., L.W., J.E.K., L.L., Y.L., P.W., M.M., S.M., L.M., and N.R.W. are inventors on patents related to IL-6. P.S.H. is an employee of Foundation Medicine Inc. K.H. is an employee of Roche Products Ltd. D.F.M. reports a consulting/advisory role for Bristol-Myers Squibb, Merck, Roche/Genentech, Pfizer, Exelixis, Novartis, Eisai, X4 Pharmaceuticals, and Array BioPharma; he also reports that his home institution receives research funding from Prometheus Laboratories. T.P. reports honoraria and consulting/advisory roles with Roche/Genentech, Bristol-Myers Squibb, and Merck; consulting/advisory role with AstraZeneca and Novartis; research funding from AstraZeneca/MedImmune and Roche/Genentech; and other relationships with Ipsen and Bristol-Myers Squibb. L.E. reports honoraria from or consulting/advisory roles with AbbVie, Amgen, AstraZeneca, Bayer, Bristol Meyers Squibb, Celgene, Chugai, eTHeRNA, Genentech, Gritstone, Medimmune, Molecuvax, Macrogenics, Novartis, Peregrine, Replimune, Roche, Silverback, Syndax, and Vaccinex; she reports that her home institution receives funding from Aduro Biotech, AstraZeneca, Breast Cancer Research Foundation, Bristol Meyers Squibb, Corvus, Department of Defense, EMD Serono, Genentech, HeritX, Inc., Maxcyte, Merck, National Cancer Institute, NSABP Foundation, Roche, Tempest, Translational Breast Cancer Research Consortium. J.E.R. has received non-financial support from Roche Genentech and consulting fees from Agensys, Eli Lilly, Sanofi, and Oncogene., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)