Immune Reconstitution following High-Dose Chemotherapy and Autologous Stem Cell Transplantation with or without Pembrolizumab Maintenance Therapy in Patients with Lymphoma

Abstract

Autologous stem cell transplantation (ASCT) is a standard of care for patients with chemosensitive, relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and diffuse large B cell lymphoma (DLBCL). Whereas the clinical benefit of ASCT has traditionally been attributed solely to cytoreduction from intensive chemotherapy, ASCT has important immunogenic effects that may contribute to its antitumor efficacy and could provide a favorable immune environment for post-ASCT immune-based maintenance treatments. We previously reported clinical results of a phase II trial (ClinicalTrials.gov identifier NCT02362997) testing 8 doses of pembrolizumab maintenance therapy after ASCT for patients with R/R cHL or DLBCL. To clarify the impact of pembrolizumab on immune reconstitution, we compared the kinetics of peripheral blood immune cell recovery after ASCT for trial patients receiving pembrolizumab maintenance to those of a contemporaneous control cohort of similar patients undergoing ASCT without pembrolizumab maintenance. This study was conducted to characterize the impact of post-ASCT pembrolizumab maintenance therapy on immune reconstitution for patients with R/R DLBCL and cHL and to identify candidate biomarkers of efficacy and immune-related adverse events (irAEs). Peripheral blood (PB) mononuclear cell samples were prospectively collected at 1 to 18 months after ASCT and analyzed by flow cytometry using a panel of fluorophore-conjugated monoclonal antibodies to identify B cells, natural killer (NK) cells, and various dendritic cell (DC) and T cell subsets. A median of 5 (range, 1 to 8) post-ASCT PB samples were collected from 144 patients (59 in the pembrolizumab group and 85 in the control group). Clinical characteristics of the 2 cohorts were similar. Compared with cHL patients, DLBCL patients (all of whom received anti-CD20 monoclonal antibody therapy before ASCT) had delayed CD19+ cell reconstitution that persisted for at least 18 months after ASCT. No other differences in immune reconstitution based on lymphoma subtype were observed. Post-ASCT pembrolizumab maintenance therapy was associated with an elevation in circulating DCs (driven by higher levels of plasmacytoid and immature DCs) that persisted for the duration of pembrolizumab treatment, along with a significant reduction in PD-1+ T cells that persisted for 6 to 12 months after completion of pembrolizumab therapy. Despite the key role of T cells in mediating the effects of PD-1 blockade, pembrolizumab maintenance did not affect recovery of any T cell subsets. In an exploratory analysis, a higher baseline CD4+ terminal effector memory cell count (defined as CD3+CD4+CD45RA+CD62L-) was associated with inferior progression-free survival (PFS), but only among patients who received pembrolizumab maintenance (P = .003). As continuous variables, lower absolute levels of NK cells (P = .009), PD-1+ CD4+ T cells (P = .005), and PD-1+ CD8+ T cells (P = .005) before pembrolizumab initiation were each associated with a higher risk of grade 2+ irAEs. Our findings indicate that post-ACST pembrolizumab maintenance therapy is associated with a persistent elevation of circulating DCs, but its impact on the reconstitution of other immune cells in peripheral blood appears limited. Our study suggests that early features of post-ASCT immune reconstitution could be associated with PFS and the risk of irAE and warrant additional investigation. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Keywords: Autologous stem cell transplantation; Diffuse large B cell lymphoma; Hodgkin lymphoma; Immune reconstitution; PD-1; Pembrolizumab.

Conflict of interest statement

Declaration of Competing Interest R.W.M.: Consulting for Genmab; research funding from Bristol Myers Squibb and Merck. J.R.B.: Consulting for AbbVie, Acerta/Astra-Zeneca, BeiGene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, MorphoSys, Nextcea, Novartis, Pfizer, and Rigel; research funding from Gilead, Loxo/Lilly, SecuraBio, Sun, and TG Therapeutics; Data and Safety Monitoring Board for Invectys. J.L.C.: Consulting for Incyte and MorphoSys; research funding from Bayer and AbbVie. M.S.D.: Consulting for AbbVie, Adaptive Biotechnologies, Ascentage Pharma, AstraZeneca, BeiGene, BMS, Celgene, Eli Lilly, Genentech, Janssen, Takeda, and TG Therapeutics; research support from AbbVie, Ascentage Pharma, AstraZeneca, BMS, Genentech, MEI Pharma, Novartis, Surface Oncology, TG Therapeutics, and Verastem; honoraria from Research to Practice and Aptitude Health. E.J.: Consulting for Syros and Takeda; research funding from Acerta, Janssen, Novartis, and Pharmacyclics. C.A.J.: Consulting for Kite Pharma/Gilead, Novartis, BMS/Celgene, Precision Biosciences, Nkarta, bluebird bio, Epizyme, Lonza, AbbVie, and Ipsen; research funding from Kite Pharma/Gilead and Pfizer. P.B.D.: Advisory board for Kite Pharma/Gilead. Y.N.: Consulting for Affimed and Novo Nordisk; research funding from Novartis, Biosecura, Astra-Zeneca, Affimed, and Takeda. Y.-B.C.: Consulting for Incyte, Magenta, Gamida Cell, Daiichi, Equilium, Celularity, and Actinium. A.F.H.: Consulting for Bristol Myers Squibb, Genentech, Merck, Seattle Genetics, AstraZeneca, Karyopharm, ADC Therapeutics, Takeda, and Tubulis; research funding from Bristol Myers Squibb, Genentech, Merck, Seattle Genetics, Kite Pharma, Gilead Sciences, AstraZeneca, and ADC Therapeutics. P.A.: Consulting for Merck, BMS, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, Celgene, MorphoSys, Daiichi Sankyo, Miltenyi Biotech, Tessa, GenMab, C4, Enterome, Regeneron, Epizyme, Astra Zeneca, and Genentech; research funding (institutional) from Merck, BMS, Affimed, Adaptive, Roche, Tensha, Otsuka, Sigma Tau, Genentech, IGM, and Kite Pharma; honoraria from Merck and BMS. J.R.: Consulting for Akron Biotech, Blackstone Life Sciences Advisors, Clade Therapeutics, Garuda Therapeutics, Immunitas Therapeutics, LifeVault Bio, Novartis, Rheos Medicines, Talaris Therapeutics, and TScan Therapeutics; research grant support from Amgen, Equillium, Novartis, and Kite Pharma/Gilead; Data and Safety Monitoring Board for Avrobio. The other authors have no conflicts of interest to report.

Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1 –

(A) Total WBC, (B) total lymphocyte, (C) CD3+, (D) CD19+, and (E) NK cells (pembrolizumab vs control cohort). The interquartile range of healthy control patients for each cell population is depicted as a gray bar, and the median value is noted with a dashed line.

Figure 2 –

T cell subsets – (A) CD4+ T cells, (B) CD8+ T cells, (C) Tregs, (D) CD4 T con, (E) Treg:Tcon, (F) Treg:CD8 (pembrolizumab vs control cohort). The interquartile range of healthy control patients for each cell population is depicted as a gray bar, and the median value is noted with a dashed line.

Figure 3 –

Heat map of naïve, central memory (CM), effector memory (EM), and terminally differentiated effector (TEMRA) CD4+ and CD8+ T cells (pembrolizumab vs control cohort). T cell subsets were quantified at multiple post-ASCT timepoints (1, 2, 3, 6, 12, and 18 months) among patients in the control and pembrolizumab cohorts. The absolute number of cells identified is displayed as a heatmap where blue, white, and red represent values less than, equal to, and greater than those of healthy donors. Significant differences between the control and pembrolizumab cohorts are marked with *. No significant differences between the two cohorts were observed during pembrolizumab treatment (i.e. at the 2, 3, and 6 month timepoints). Full recovery of multiple T cell subsets (represented in blue) was not achieved even 18 months following ASCT.

Figure 4 –

(A) Total circulating dendritic cells, (B) plasmacytoid DCs, (C) myeloid DCs, (D) CD123−/CD11c− DCs (pembrolizumab vs control cohort). The interquartile range of healthy control patients for each cell population is depicted as a gray bar, and the median value is noted with a dashed line.

Figure 5 –

(A) PD-1+ CD4+, (B) PD-1+ CD8+ T cells (pembrolizumab vs control cohort). The interquartile range of healthy control patients for each cell population is depicted as a gray bar, and the median value is noted with a dashed line.