Purpose: B-cell maturation antigen (BCMA)-chimeric antigen receptor T-cells (CART) improve results obtained with conventional therapy in the treatment of relapsed/refractory multiple myeloma. However, the high demand and expensive costs associated with CART therapy might prove unsustainable for health systems. Academic CARTs could potentially overcome these issues. Moreover, response biomarkers and resistance mechanisms need to be identified and addressed to improve efficacy and patient selection. Here, we present clinical and ancillary results of the 60 patients treated with the academic BCMA-CART, ARI0002h, in the CARTBCMA-HCB-01 trial. Patients and Methods: We collected apheresis, final product, peripheral blood and bone marrow samples before and after infusion. We assessed BCMA, T-cell subsets, CART kinetics and antibodies, B-cell aplasia, cytokines, and measurable residual disease by next-generation flow cytometry, and correlated these to clinical outcomes. Results: At cut-off date March 17, 2023, with a median follow-up of 23.1 months (95% CI, 9.2–37.1), overall response rate in the first 3 months was 95% [95% confidence interval (CI), 89.5–100]; cytokine release syndrome (CRS) was observed in 90% of patients (5% grades ≥3) and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in 2 patients (3%). Median progression-free survival was 15.8 months (95% CI, 11.5–22.4). Surface BCMA was not predictive of response or survival, but soluble BCMA correlated with worse clinical outcomes and CRS severity. Activation marker HLA-DR in the apheresis was associated with longer progression-free survival and increased exhaustion markers correlated with poorer outcomes. ARI0002h kinetics and loss of B-cell aplasia were not predictive of relapse. Conclusions: Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes.

Enhancing our comprehension of mRNA vaccines may facilitate the future design of novel vaccines aimed at augmenting immune protection while minimising reactogenic responses. Before this design is carried out, it is important to determine whether adaptive immunity correlates with the reactogenicity profile of vaccines. We studied a large cohort that was vaccinated with mRNA vaccines to answer this question. This was an observational study with real-world data. Reactogenicity data were obtained from the VigilVacCOVID study. Immunogenicity (humoral and cellular) data were retrieved from health records. One main population (n = 215) and two subpopulations were defined (subpopulation 1, n = 3563; subpopulation 2, n = 597). Sensitivity analyses were performed with subpopulations 1 and 2 to explore the consistency of results. We analysed the association of the intensity and types of adverse reactions with the development and quantity of elicited antibody titres. As an exploratory analysis in subpopulation 1, we assessed the association between reactogenicity and cellular immunogenicity. A higher incidence of fever, malaise, and myalgia including severe cases was significantly associated with the development and quantity of positive antibody titres. No significant findings were observed with cellular immunity. We observed a positive association between immunogenicity and reactogenicity. These findings can be relevant for the future development of our understanding of how mRNA vaccines function.

Background The comparative safety profile of SARS-Cov2 vaccines requires further characterization in real-world settings. Objectives The aim of the VigilVacCOVID study was to assess the short-term safety of BNT162b2 and mRNA-1273 during the vaccination campaign of healthcare professionals (HCPs) and solid-organ transplant recipients (SOTRs) at a hospital clinic. Methods We conducted an observational, prospective, single-center, post-authorization study to characterize short-term adverse reactions (ARs) after vaccination. The primary endpoint was to assess between-vaccine differences (HCPs receiving BNT162b2 or mRNA-1273) and between-population differences (HCPs and SOTRs, both receiving mRNA-1273) in the risk of any ARs. Propensity score and covariate-adjusted multivariate models were used. The key secondary endpoint was to provide a descriptive assessment of the frequencies and intensity distribution of ARs. Results We included 5088 HCPs and 1289 patients. mRNA-1273 showed greater reactogenicity than BNT162b2, with an odds ratio (OR) for any AR of 3.04 (95% confidence interval (CI) 2.48–3.73; p value: < 0.001) and a higher frequency and intensity of reported ARs. Compared with HCPs vaccinated with mRNA-1273, SOTRs showed a lower risk of ARs (OR = 0.36; 95% CI 0.25–0.50), with fewer and less severe ARs. Age, sex, and previous SARS-CoV-2 infection were statistically significant covariates for the risk of any AR. A history of drug allergy was significant in the comparison between vaccines (BNT162b2 vs. mRNA-1273), but not in that between SOTRs and HCPs. Conclusions Our study shows that mRNA-1273 had greater reactogenicity than BNT162b2. Overall, both vaccines had an adequate tolerability profile. mRNA-1273 vaccination caused fewer ARs with milder severity in SOTRs.

Table 5. Cox regression analysis of the impact of the levels of cytokines in progressionfree (PFS) and overall survival (OS).