{"doi":"10.1111/bjh.17397","title":"B‐cell maturation antigen chimeric antigen receptor T‐cell re‐expansion in a patient with myeloma following salvage programmed cell death protein 1 inhibitor‐based combination therapy","abstract":"Autologous T cells expressing a chimeric antigen receptor (CAR) specific for B-cell maturation antigen (BCMA) have demonstrated high response rates in refractory myeloma,1-3 but relapses remain common. Mechanisms of relapse may be T-cell intrinsic (e.g. terminal differentiation, exhaustion), tumour-cell intrinsic (e.g. antigen loss) and/or microenvironment-intrinsic (e.g. upregulation of inhibitory ligands or immunosuppressive cell populations). One approach to overcome T-cell- and microenvironment-intrinsic failure is blockade of the programmed cell death protein 1(PD-1)–programmed death-ligand 1 (PD-L1) axis. PD-1 expression increases on activated CAR T cells following infusion into patients,3, 4 and T-cell-produced interferon γ can increase PD-L1 expression within the tumour microenvironment.5 Disruption of this axis enhances CAR T-cell activity preclinically,6, 7 and administration of anti-PD-1 antibody re-expanded CAR T cells and induced responses in a subset of patients with diffuse large B-cell lymphoma failing to respond or progressing after cluster of differentiation 19 (CD19)-directed CAR T cells.8 Preliminary safety has also been demonstrated combining PD-1 blockade with the bispecific T-cell engager blinatumumab in acute lymphoblastic leukaemia.9 While the role of PD-1/PD-L1 blockade in myeloma remains controversial,10-12 the potentially positive impact of PD-1/PD-L1 blockade on CAR T-cell activity might merit re-exploration of this strategy in conjunction with CAR T-cell therapy for myeloma. We previously described outcomes of 25 patients with relapsed/refractory myeloma treated in three cohorts on a phase I trial (NCT02546167) between 11/2015 and 11/2017 with BCMA-directed CAR T-cell therapy (CART-BCMA).2 We retrospectively reviewed post-progression therapies and identified five patients who received a PD-1 inhibitor-based combination as their next therapy after CAR T cells. Responses were determined by International Myeloma Working Group (IMWG) criteria. Peripheral blood CAR T-cell levels were measured by quantitative polymerase chain reaction (qPCR) and flow cytometry, as described,2 pretreatment, 2–4 weeks after first dose and every 4 weeks until progression. All patients still had CART-BCMA cells detectable by qPCR at initiation of salvage therapy. Adverse events were assessed by retrospective chart review. Assessment of T-cell activation and immune checkpoint molecule expression was performed by flow cytometry, as described.2, 13 The study was approved by the University of Pennsylvania Institutional Review Board and informed consent was obtained for each patient. Patient characteristics are shown in Table I. All five had highly refractory, poor-risk disease, progressed at a median (range) of 2 (1–4) months after CART-BCMA, and initiated anti-PD-1-based combination therapy at a median (range) of 4 (1–5) months after CART-BCMA. All were refractory to prior pomalidomide (Pom) and two were refractory to a prior PD-1 inhibitor. All patients received the anti-PD-1 antibody pembrolizumab in combination with dexamethasone (Dex) and either lenalidomide (Len) or Pom; four also received the anti-SLAMF7 antibody elotuzumab (Elo). Dosing/schedule of drugs is described in Table I. Of the five patients identified, one patient (07) with rapidly proliferative, kappa light chain myeloma had a brief but significant CART-BCMA re-expansion on day 65, 2 weeks after starting Pembro/Elo/Pom/Dex, as indicated by >20-fold increase in circulating CAR transgene levels by qPCR and a corresponding increase in CAR T cells by flow cytometry (Fig 1A). The CART re-expansion coincided with a short-lived, minimal response (MR) to therapy (35% reduction in the difference between involved and uninvolved free light chain), although free kappa light chains started rising again within 3 weeks. Given that his myeloma was previously refractory to Pembro, Pom, and Dex, it seems likely that the response was due to expansion of CART activity, with poten","journal":"British Journal of Haematology","year":2021,"id":192768,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.963,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":526746,"name":"Lifeng Tian","orcid":"0000-0001-9740-5327","position":1,"is_corresponding":false},{"id":615861,"name":"Alfred L. Garfall","orcid":"0000-0003-2791-5748","position":2,"is_corresponding":false},{"id":325454,"name":"J. Joseph Melenhorst","orcid":"0000-0001-7677-537X","position":3,"is_corresponding":false},{"id":105473,"name":"Simon F. Lacey","orcid":"0000-0003-2882-1962","position":4,"is_corresponding":false},{"id":459220,"name":"Edward A. Stadtmauer","orcid":"0000-0002-3935-6069","position":5,"is_corresponding":false},{"id":550342,"name":"Dan T. Vogl","orcid":"0000-0002-2935-2566","position":6,"is_corresponding":false},{"id":759999,"name":"Vanessa Gonzalez","orcid":"0000-0003-3603-7457","position":7,"is_corresponding":false},{"id":325455,"name":"Gabriela Plesa","orcid":"0000-0002-4279-5943","position":8,"is_corresponding":false},{"id":247164,"name":"Regina M. Young","orcid":"0000-0002-0158-9449","position":9,"is_corresponding":false},{"id":760000,"name":"Adam Waxman","orcid":"0000-0001-5217-1221","position":10,"is_corresponding":false},{"id":256649,"name":"Bruce L. Levine","orcid":"0000-0001-6971-8465","position":11,"is_corresponding":false},{"id":227870,"name":"Carl H. June","orcid":"0000-0003-0241-3557","position":12,"is_corresponding":false},{"id":242813,"name":"Michael C. Milone","orcid":"0000-0002-1580-9844","position":13,"is_corresponding":false},{"id":526856,"name":"Adam D. Cohen","orcid":"0000-0003-0939-3843","position":14,"is_corresponding":false},{"id":649473,"name":"Luca Bernabei","orcid":"0000-0002-0213-8914","position":0,"is_corresponding":true}],"reference_count":15,"raw_metadata":null,"created_at":"2026-07-18T23:49:43.496702Z","pmid":"33713436","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}