2186: Cellular and Humoral Responses Following SARS-CoV-2 mRNA Vaccination in Patients on PD-1 Immunotherapy with irAEs

Sokratis Apostolidis¹, Paulina Coutifaris², Mark Painter³, Ajinkya Pattekar², Rishi Goel¹, divij mathew², Wenzhao Meng², Kevin Wang², Bria Fulmer², Angela Corrigan², Kendall Lundgreen², Elizabeth Drapeau², Derek Oldridge², Josephine Giles², Amy Baxter², Sasikanth Manne², Michelle Mckeague², Ahron Flowers², Oliva Kuthuru², Sherea Long², Jeanette Dougherty², Sigrid Gouma², Justine Williams², Maura McLaughlin², Sharon Adamski², Alba Grifoni⁴, Daniela Weiskopf⁴, Alessandro Sette⁴, Scott Hensley², Paul Bates², Eline Luning Prak¹, Laura Vella², Giorgos Karakousis², Ravi Amaravadi², Suzanne McGettigan², Kristin Kreider², Tara Mitchell², Allison Greenplate², Lynn Schuchter², Alexander Huang² and E. John Wherry¹, ¹University of Pennsylvania, Philadelphia, PA, ²UPenn, Philadelphia, ³UPenn, Philadelphia, PA, ⁴LJI, La Jolla

Background/Purpose: Patients with cancer exhibit increased mortality from SARS-CoV-2 infection compared to the general population. SARS-CoV-2 mRNA vaccination in healthy individuals generates effective and long-lasting immune protection against COVID-19. PD-1 is highly expressed on the surface of T follicular helper cells that play a central role in T cell dependent B cell vaccine responses. Here, we sought to investigate the cellular and humoral responses in patients on PD-1 immunotherapy after SARS-CoV-2 mRNA vaccination, with a particular focus on patients developing immune-related adverse events (irAEs).

Methods: We investigated the longitudinal induction of antigen-specific antibody, B cell and T cell responses in patients with melanoma on anti-PD-1 immunotherapy (aPD-1, n = 44) receiving a 2-dose SARS-CoV-2 mRNA vaccine regimen during 6 distinct timepoints over the course of 9 months (Figure 1). We compared these responses against an established cohort of healthy control individuals (HC, n=45). All individuals included in this study were not previously infected with SARS-CoV-2. Incidence of irAEs in the aPD-1 patients was determined with retrospective chart review.

Results: After a 2-dose mRNA vaccine regimen, a-PD1 patients had lower levels of anti-Spike IgG after the first vaccine dose (V2) and lower levels of anti-Receptor Binding Domain (RBD) IgG after the first and second dose (V2 and V4) compared to healthy controls (Figure 2). Within the aPD-1 patient group, patients with irAEs demonstrated a trend towards lower anti-Spike and anti-RBD IgG compared to patients with no irAEs (Figure 3). Vaccine-specific memory B cells (mBCs) recognizing Spike and RBD were generated in patients on aPD-1 therapies to an extent equivalent to healthy controls. The mBCs from aPD-1 patients efficiently recognized the Alpha, Beta and Delta variants of concern (VOC) of SARS-CoV-2 but exhibited diminished recognition of the Omicron variant at 2 months after the 2^nd vaccination (V5). This defect improved over time, with mBCs from aPD-1 patients recognizing the Omicron VOC at levels similar to the control group by 6-9 months following primary vaccination (V6). Finally, using a peptide pool of the wild-type Spike protein, we found that all aPD-1 patients generated antigen-specific CD4 and CD8 T-cell responses following vaccination. Nevertheless, when tested with an omicron-specific peptide pool, the abundance of antigen-specific CD4 T cells, but not CD8 T cells, from patients on aPD-1 immunotherapy was lower than that of healthy controls.

Conclusion: These results indicated that patients on aPD-1 immunotherapeutics generate productive humoral and cellular vaccine-specific responses against the wild-type Spike protein following SARS-CoV-2 mRNA vaccination. However, they also demonstrated diminished B cell and CD4 T cell recognition of the immune-evasive Omicron variant. In addition, patients with irAEs showed some of the lower serological responses among all the individuals tested. The qualitative defects seen in patients on aPD-1 therapy highlight the importance of the PD-1 pathway in promoting fully functional vaccine responses, suggesting possibly a more pressing need for these patients to receive booster vaccinations.
Figure 1. Schematic representation of the study design and blood draw schedule.

Figure 2. Anti-Spike (left) and anti-RBD (right) IgG in the healthy and the aPD-1 melanoma groups. The two groups were compared with non-parametric testing (Wilcoxon test) at each timepoint with Benjamini-Hochberg correction applied for multiple comparisons. * < 0.05 and ** < 0.01.

Figure 3. Anti-RBD IgG shown for aPD-1 patients without (red) and with (blue) history of irAEs.
Disclosures: S. Apostolidis, None; P. Coutifaris, None; M. Painter, None; A. Pattekar, None; R. Goel, None; d. mathew, None; W. Meng, None; K. Wang, None; B. Fulmer, None; A. Corrigan, None; K. Lundgreen, None; E. Drapeau, None; D. Oldridge, None; J. Giles, None; A. Baxter, None; S. Manne, None; M. Mckeague, None; A. Flowers, None; O. Kuthuru, None; S. Long, None; J. Dougherty, None; S. Gouma, None; J. Williams, None; M. McLaughlin, None; S. Adamski, None; A. Grifoni, None; D. Weiskopf, None; A. Sette, None; S. Hensley, None; P. Bates, None; E. Luning Prak, None; L. Vella, None; G. Karakousis, None; R. Amaravadi, None; S. McGettigan, None; K. Kreider, None; T. Mitchell, None; A. Greenplate, None; L. Schuchter, None; A. Huang, None; E. Wherry, Merck/MSD, Janssen, Surface Oncology, Synthekine.