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Purpose: Metastatic breast cancer patients are the most prevalent oncology population with advanced disease facing COVID-19 pandemic. Immune responses after mRNA-based vaccination during treatment with CDK4/6 inhibitors or HER2-directed agents remain unclear. We conducted a prospective analysis to elucidate changes in antibody titers and lymphocyte counts following full course of mRNA-BNT162b2 (tozinameran) vaccination in recipients undergoing these targeted therapies., Methods: Patients who had received a booster dosing and had been treated for at least 6 months were eligible. Antibody titers against SARS-CoV-2 spike protein were measured at four subsequent time points. Immunophenotyping of circulating lymphocytes was performed before the third dose of tozinameran and four weeks later to quantify the absolute counts of CD3 + CD4 + T-helper cells, CD3 + CD8 + T-cytotoxic cells, CD19 + B cells, and CD56 + CD16 + NK cells. We also assessed the incidence of breakthrough infections and investigated whether immune changes affect time-to-treatment failure (TTF) after booster vaccination., Results: The current analysis included 69 patients, of whom 38 (55%) and 31 (45%) were being treated with CDK4/6 inhibitors and HER2-targeted therapies, respectively. All participants received a third dose of tozinameran between September 23 and October 7, 2021. Multivariate analysis revealed that CDK4/6 inhibition predicted a significantly impaired humoral response after the booster dose. This detrimental effect was also evident for T-helper cell counts before the third immunization, but it disappeared in the subsequent evaluation. After a median follow-up of 22.3 months, we observed 19 (26%) cases of COVID-19 outbreaks, all experiencing favorable clinical outcomes. Univariate analysis showed a significant association between the onset of SARS-CoV-2 infections and the use of CDK4/6 inhibitors, as well as with an impaired antibody and T-helper cell response. Only the last two covariates remained independent predictors after multivariate testing. Dynamic variations in antibody titers and T-helper cell counts did not affect TTF in multivariate regression analysis., Conclusions: Our results confirm that the immune response to tozinameran is impaired by CDK4/6 inhibitors, increasing the odds of breakthrough infections despite the third vaccine dose. Current evidence recommends maintaining efforts to provide booster immunizations to the most vulnerable cancer patients, including those with advanced breast cancer undergoing CDK4/6 inhibition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Nelli, Fabbri, Botticelli, Giannarelli, Marrucci, Fiore, Virtuoso, Berrios, Scagnoli, Pisegna, Cirillo, Panichi, Massari, Silvestri and Ruggeri.)

Background: Immunosuppressive dosing of corticosteroids at the start of treatment impairs immune checkpoint inhibitor (ICI) efficacy in advanced non-small cell lung cancer (NSCLC). Previous cumulative dose and intake modality of corticosteroids may result in different levels of immunosuppression. We sought to determine whether these aspects could predict disease control and survival in NSCLC patients receiving ICIs., Methods: We conducted a retrospective single-center study, including patients treated with ICI as second-line therapy at our institution between July 2015 and February 2021. A prednisone equivalent threshold of 700 mg defined low (LCD) or high (HCD) cumulative dosing during the 90 days before starting ICIs. At least one 5-day course of ≥ 10 mg prednisone equivalent determined whether the intake was pulse (PCD, ≤ 5 days) or continuous (CCD, > 5 days)., Results: We included 113 consecutive patients. Durable control benefit and no clinical benefit (NCB) were reported in 53 (47%) and 60 (53%) of the cases, respectively. ECOG PS 1-2, negative PD-L1 expression, HCD, and CCD were significantly related to NCB in multivariate analysis. The median PFS was 4.6 months (95%CI: 3.9-6.3) and median OS was 6.9 months (95% CI: 6.0-8.9) after a median follow-up time of 43.5 months (95% CI: 32.6-54.4). Multivariate analysis of survival confirmed ECOG PS 1-2 (p = 0.005), negative PD-L1 expression (p = 0.002), and CCD (p = 0.001) significantly correlated with an increased risk of mortality., Conclusions: These findings imply that immunosuppressive corticosteroid dosing before ICIs, even of short duration, might affect survival. The constraints of this study and lack of reliable comparisons suggest a hypothesis-generating value of these results., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Here, we developed an unbiased, functional target-discovery platform to identify immunogenic proteins from primary non-small cell lung cancer (NSCLC) cells that had been induced to apoptosis by cisplatin (CDDP) treatment in vitro, as compared with their live counterparts. Among the multitude of proteins identified, some of them were represented as fragmented proteins in apoptotic tumor cells, and acted as non-mutated neoantigens (NM-neoAgs). Indeed, only the fragmented proteins elicited effective multi-specific CD4 + and CD8 + T cell responses, upon a chemotherapy protocol including CDDP. Importantly, these responses further increased upon anti-PD-1 therapy, and correlated with patients' survival and decreased PD-1 expression. Cross-presentation assays showed that NM-neoAgs were unveiled in apoptotic tumor cells as the result of caspase-dependent proteolytic activity of cellular proteins. Our study demonstrates that apoptotic tumor cells generate a repertoire of immunogenic NM-neoAgs that could be potentially used for developing effective T cell-based immunotherapy across multiple cancer patients.