ABSTRACT
Background: The two FDA approved mRNA-based SARS-CoV2 vaccines have shown >90% efficacy at preventing COVID and eliciting protective immunity in nearly all healthy individuals. However, the extent of vaccine induced antibody and T cell immunity in immunocompromised patients is not well known. Our study objective is to determine if patients with hematologic malignancies treated with B-cell targeting chimeric antigen receptor (CAR) T cell therapies can mount antibody and T cell immune responses to SARS-CoV2 vaccines. A prospective single-center study to evaluate the SARS-CoV2 immune responses in immunocompromised individuals (COVAX Study) was initiated at University of Pennsylvania following the IRB guidelines. The study enrolled 8 healthy adults,12 patients are in remission after treatment (average of 40.6 months) with CART cells targeting either CD19 or CD19+CD22 and received both doses of SARS-CoV2 vaccine. Methods and Results: Serology to SARS-CoV2 spike-receptor binding domain (RBD) IgG, RBD-IgA, RBD-IgM and spike-specific T cell responses were measured prior to vaccination and serially up to 28 days after booster vaccination. RBD-IgG and RBD-IgA were detected in 8/8 and 7/8 healthy subjects compared to 5/12 and 2/12 CART patients, respectively (Figure A). In the CART cohort, several patients who demonstrated an induction of RBD-IgG (57.2/uL +/- 20.2) compared to those who were RBD-IgG-negative (9/uL +/- 10.1, ANOVA with multiple comparisons test p=0.017) have higher level of circulating B cells. No association was found with time since CART infusion, age, disease type, or vaccine manufacturer. All 8 healthy subjects demonstrated induction of SARS-Cov2 spike-specific CD4 + T cell immunity compared to 7 out of 11 CART patients (Figure B). RBD-IgG responses were not correlated with CD4 + T cell activation (Pearson correlation, R=0.21, p=0.53). Indeed, 3 CART patients demonstrated robust CD4 + T cell activation despite absence of antibody induction. Overall, 8/12 CART patients demonstrated induction of either or both humoral and T cell immune responses. Conclusions: We show that immune responses to SARS-CoV2 mRNA vaccines are induced in majority of patients who have been treated with CART therapies targeting B-cell lineage antigens. Induction of vaccine-specific antibody was strongly associated with the level of circulating B cells. However, in CART cohort patients despite severe humoral immune deficiency, strong CD4 + T cell responses were observed suggestive of a sufficient protective immunity. [Formula presented] Disclosures: Frey: Novartis: Research Funding;Sana Biotechnology: Consultancy;Kite Pharma: Consultancy;Syndax Pharmaceuticals: Consultancy. Garfall: Amgen: Honoraria;CRISPR Therapeutics: Research Funding;GlaxoSmithKline: Honoraria;Janssen: Honoraria, Research Funding;Novartis: Research Funding;Tmunity: Research Funding. Porter: American Society for Transplantation and Cellular Therapy: Honoraria;Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months;ASH: Membership on an entity's Board of Directors or advisory committees;DeCart: Membership on an entity's Board of Directors or advisory committees;Incyte: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees;Kite/Gilead: Membership on an entity's Board of Directors or advisory committees;National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding;Tmunity: Patents & Royalties;Wiley and Sons Publishing: Honoraria. June: AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy;Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company;Novartis: Patents & Royalties.
ABSTRACT
Background Pharmacologic immunosuppression and incomplete immune reconstitution after allogeneic stem cell transplant (alloSCT) may impair a patient's ability to mount an immune response to vaccines, including currently available COVID-19 vaccines. Since immunocompromised patients are susceptible to severe COVID-19 and likely to respond poorly to vaccination, we sought to characterize SARS-CoV-2 antibody responses after vaccination in alloSCT patients to determine predictors of serologic response, which may inform timing of vaccine administration. Methods This retrospective analysis included adult patients who underwent alloSCT at the University of Pennsylvania between 1/1/2019 and 1/1/2021. Chart review identified patients who had received COVID-19 vaccines and had post-vaccination antibody titers drawn by July 2021 as part of routine care (n=63). Antibodies to SARS-CoV-2 spike protein receptor binding domain were detected using an assay developed at the Hospital of the University of Pennsylvania. Variables analyzed include interval between transplant date and initial vaccination, active GVHD, concurrent immunosuppressive therapy, absolute CD4 count greater than or equal to 200 cells/mm3 peri-vaccination, and total IgG greater than or equal to 400 mg/dL peri-vaccination. Immunosuppressive therapy was defined as tacrolimus, rituximab, ruxolitinib, prednisone 10 mg daily or greater, or extracorporeal photopheresis. Predictors of positive antibody response were assessed using a multivariate, binary logistic regression. Results Median transplant to vaccine interval was 458 days (range 125 to 813) for the 63 vaccinated patients with serologies available. GVHD was present in 23/63 (37%), and 19/63 (30%) were receiving immunosuppressive therapies at the time of vaccination. CD4 count greater than 200 cells/mm3 was observed in 49 patients (78%), and total IgG greater than 400 mg/dL was observed in 51 patients (81%). In total, 50/63 patients (79%) were positive for SARS-CoV-2 IgG antibodies. Positive serologies were observed in 41/49 (84%) with CD4 counts greater than 200 cells/mm3, compared to 9/14 (64%) with CD4 less than 200 cells/mm3. Our model found that peri-vaccination CD4 count greater than 200 cells/mm3 was a significant predictor of positive SARS-CoV-2 IgG serologies in this population (OR 2.14, 97.5% CI = 0.7 to 3.8, p= 0.005). Transplant to vaccine interval, total IgG levels, GVHD status, and immunosuppressive therapies were not significant predictors of serologic response. As of July 2021 no patients had developed COVID-19 after vaccination, regardless of serologic response. Conclusions This retrospective observational study demonstrates that the majority of alloSCT patients vaccinated against COVID-19 within 2 years of transplant, including those with active GVHD and on immunosuppressive therapies, can mount serologic responses. CD4 count greater than 200 cells/mm3 is a significant predictor of positive serologic response, though even among patients with CD4 counts under 200 cells/mm3 over 60% developed SARS-CoV-2 IgG antibodies. Disclosures: Perry: Incyte: Consultancy, Speakers Bureau;Abbvie,: Speakers Bureau;Kadmon: Consultancy. Pratz: University of Pennsylvania: Current Employment;Abbvie: Consultancy, Honoraria, Research Funding;Astellas: Consultancy, Honoraria, Research Funding;Cellgene: Consultancy, Honoraria;Novartis: Consultancy;BMS: Consultancy, Honoraria;Agios: Consultancy;Millenium: Research Funding. Luger: Syros: Honoraria;Agios: Honoraria;Daiichi Sankyo: Honoraria;Jazz Pharmaceuticals: Honoraria;Brystol Myers Squibb: Honoraria;Acceleron: Honoraria;Astellas: Honoraria;Pfizer: Honoraria;Onconova: Research Funding;Celgene: Research Funding;Biosight: Research Funding;Hoffman LaRoche: Research Funding;Kura: Research Funding. Perl: Astellas: Consultancy, Research Funding;Loxo: Consultancy;AbbVie: Consultancy, Research Funding;Syndax: Consultancy;BMS/Celgene: Consultancy;Roche: Consultancy;Fujifilm: Research Funding;Daiichi Sankyo: Consultancy, Research Funding;Forma: Consult ncy;Arog: Research Funding;Genentech: Consultancy;Actinium: Consultancy;Onconova: Consultancy;Sumitomo Dainippon: Consultancy. Porter: ASH: Membership on an entity's Board of Directors or advisory committees;Incyte: Membership on an entity's Board of Directors or advisory committees;DeCart: Membership on an entity's Board of Directors or advisory committees;Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months;American Society for Transplantation and Cellular Therapy: Honoraria;Kite/Gilead: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees;National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding;Tmunity: Patents & Royalties;Wiley and Sons Publishing: Honoraria. Hexner: Blueprint medicines: Membership on an entity's Board of Directors or advisory committees, Research Funding;PharmaEssentia: Membership on an entity's Board of Directors or advisory committees;Tmunity Therapeutics: Research Funding. Frey: Sana Biotechnology: Consultancy;Kite Pharma: Consultancy;Syndax Pharmaceuticals: Consultancy;Novartis: Research Funding.