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This article examines the use of tyrosine kinase inhibitor (TKI) therapy as a maintenance treatment after chimeric antigen receptor (CAR) T-cell therapy in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who cannot undergo allogeneic hematopoietic cell transplantation (alloHCT). The study presents a case series of seven patients who received CAR-T cells for relapsed/refractory Ph+ ALL and subsequently received TKI maintenance. The article discusses the patients' characteristics and outcomes, emphasizing the need for further research and data on this approach. The study suggests that TKI maintenance therapy after CAR-T may be beneficial, particularly in patients who achieve complete molecular remission (CMR) and have no evidence of minimal residual disease (MRD). The authors recommend larger prospective trials to confirm the effectiveness and safety of TKI maintenance therapy post-CAR-T, and to explore its potential application to other subtypes of ALL. [Extracted from the article]

Summary: Emerging biological and clinical data, along with advances in new technologies, have exposed the mechanistic diversity in post‐haematopoietic stem cell transplant (HCT) relapse. Post‐HCT relapse mechanisms are relevant for guiding sophisticated selection of therapeutic interventions and identification of areas for further research. Clonal evolution and emergence of resistant leukemic strains is a common mechanism shared by relapse post‐chemotherapy and post‐HCT, other mechanisms such as leukemic immune escape and donor T cell exhaustion are unique entities to post‐HCT relapse. Due to diversity in the mechanisms behind post‐HCT relapse, the subsequent clinical approach relies on clinician discretion, rather than objective evidence. Lack of standardized selection based on post‐HCT relapse mechanism(s) could be a contributing factor to observed poor outcomes. Therapeutic strategies including donor lymphocyte infusion (DLI), second transplant, immunotherapies, hypomethylating agents, and targeted strategies are supported options and efficacy may be enhanced when post‐HCT AML relapse mechanism is established and guides treatment selection. This review aims, through compilation of supporting studies, to describe mechanisms of post‐HCT relapse and their implications for subsequent treatment selection and inspiration for future research. [ABSTRACT FROM AUTHOR]

Summary: Increasing evidence suggests multilineage cytopenias (also known as Evans syndrome) may be caused by inborn errors of immunity (IEI) with immune dysregulation. We studied a patient with autoimmune haemolytic anaemia and immune thrombocytopenia and identified a germline mutation in SASH3 (c.862C>T;p.Arg288Ter), indicating a recently identified IEI. Immunohistochemistry performed after clinically indicated splenectomy revealed severe hypoplasia/absence of germinal centres. The autoimmune phenotype was associated with an increased CD21lowT‐bet+CD11c+ subset along with decreased regulatory T cells, impaired T‐cell proliferation and T‐cell exhaustion. The younger brother carries the same SASH3 mutation and shares immunophenotypic features but is currently clinical asymptomatic, indicating heterogeneity of SASH3 deficiency. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor‐T (CAR‐T) therapies represent a major breakthrough in cancer medicine, given the ex vivo‐based technology that harnesses the power of one's own immune system. These therapeutics have demonstrated remarkable success for relapsed/refractory B‐cell lymphomas. Although more than a decade has passed since the initial introduction of CAR‐T therapeutics for patients with leukaemia and lymphoma, there is still significant debate as to where CAR‐T therapeutics fit into the management paradigm, as consensus guidelines are limited. Competing interventions deployed in subsequent lines of therapy for aggressive lymphoma include novel targeted agents, bispecific antibodies, and time‐honoured stem cell transplant. In this focused review, we discuss the major obstacles to advancing the therapeutic reach for CAR‐T products in early lines of therapy. Such barriers include antigen escape, "cold" tumour microenvironments, host inflammation and CAR‐T cell exhaustion. We highlight solutions including point‐of‐care CAR‐T manufacturing and early T lymphopheresis. We review the evidence basis for early CAR‐T deployment for B‐cell lymphomas in light of the recent Food and Drug Administration (FDA) approval of three first‐in‐class anti‐CD3/CD20 bispecific antibodies—mosunetuzumab, epcoritamab and glofitamab. We propose practical recommendations for 2024. [ABSTRACT FROM AUTHOR]

Summary: Oral azacitidine (Oral‐AZA) maintenance therapy improved relapse‐free (RFS) and overall survival (OS) significantly versus placebo for AML patients in remission after intensive chemotherapy (IC) in the phase 3 QUAZAR AML‐001 study. Immune profiling was performed on the bone marrow (BM) at remission and on‐treatment in a subset of patients with the aim of identifying prognostic immune features and evaluating associations of on‐treatment immune effects by Oral‐AZA with clinical outcomes. Post‐IC, increased levels of lymphocytes, monocytes, T cells and CD34 + CD117+ BM cells were prognostically favourable for RFS. CD3+ T‐cell counts were significantly prognostic for RFS in both treatment arms. At baseline, high expression of the PD‐L1 checkpoint marker was identified on a subset of CD34 + CD117+ BM cells; many of which were PD‐L2+. High co‐expression of T‐cell exhaustion markers PD‐1 and TIM‐3 was associated with inferior outcomes. Oral‐AZA augmented T‐cell numbers during early treatment, increased CD4+:CD8+ ratios and reversed T‐cell exhaustion. Unsupervised clustering analysis identified two patient subsets defined by T‐cell content and expression of T‐cell exhaustion markers that were enriched for MRD negativity. These results indicate that Oral‐AZA modulates T‐cell activity in the maintenance setting of AML, and these immune‐mediated responses are associated with clinical outcomes. [ABSTRACT FROM AUTHOR]

Interestingly, CAR T cells were no longer detectable by flow cytometry at day+20 after axi-cel infusion in one of the responding patients, but we observed a new expansion of CD4+ and CD8+ CAR T cells after one dose of nivolumab (at day 144 after CAR T-cell infusion). Chimeric antigen receptor-engineered (CAR) T cells have demonstrated their efficacy in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but still fail to induce a durable complete remission (CR) for most patients.[[1]] One potential mechanism of immune escape is the exhaustion of CAR T cells induced by the immunosuppressive tumour microenvironment.[[3]] The PD1/PD-L1 immune checkpoint pathway is strongly associated with CAR T-cell exhaustion.[5] The use of anti-PD1 inhibitor could generate a new CAR T-cell expansion and may improve the response.[6] We here report on 11 patients with R/R DLBCL who did not achieve CR after CD19 directed CAR T-cell therapy by axicabtagene ciloleucel (axi-cel) and who were treated subsequently with anti-PD1 nivolumab (240 mg/m SP 2 sp every 2 weeks) between 2019 and 2020. Safety and efficacy of nivolumab in patients who failed to achieve a complete remission after CD19-directed CAR T-cell therapy in diffuse large B cell lymphoma. [Extracted from the article]

Summary: The search for novel targets in chronic myeloid leukaemia (CML) is ongoing, to improve treatment efficacy in refractory disease and increase eligibility for tyrosine kinase inhibitor (TKI) discontinuation. Increased frequency of Tregs and effector Tregs was evident at diagnosis, together with increased expression of T‐cell exhaustion markers, including in regulatory T cells at diagnosis and in patients with refractory disease. Plasma analysis revealed significantly increased levels of cytokines including tumour necrosis factor (TNF)‐a and interleukin (IL)‐6 at diagnosis, in keeping with a pro‐inflammatory state prior to treatment. We hence demonstrate T‐cell exhaustion and a pro‐inflammatory state at diagnosis in CML, likely secondary to leukaemia‐associated antigenic overload associated with increased disease burden. [ABSTRACT FROM AUTHOR]

Summary: Decitabine is a DNA‐hypomethylating agent that has been widely applied for the treatment of acute myeloid leukaemia (AML) patients who are elderly or unfit for intensive therapy. Although effective, the complete response rate to decitabine is only around 30% and the overall survival remains poor. Emerging data support that regulation of DNA methylation is critical to control immune cell development, differentiation and activation. We hypothesize that defining how decitabine influences the immune responses in AML will facilitate the development of novel immune‐based leukaemia therapeutics. Here, we performed phenotypic and functional immune analysis on clinical samples from AML patients receiving decitabine treatment and demonstrated a significant impact of decitabine on the immune system. T‐cell expression of inhibitory molecules was upregulated and the ability of CD8 T cells to produce cytokines was decreased upon decitabine treatment. Importantly, in an unbiased comprehensive analysis, we identified a unique immune signature containing a cluster of key immune markers that clearly separate patients who achieved complete remission after decitabine from those who failed to do so. Therefore, this immune signature has a strong predictive value for clinical response. Collectively, our study suggests that immune‐based analyses may predict clinical response to decitabine and provide a therapeutic strategy to improve the treatment of AML. [ABSTRACT FROM AUTHOR]

Anti-PD-1 therapy can possibly reverse CAR T cells exhaustion in DLBCL Keywords: CAR T cells; diffuse large B cell lymphoma; immune checkpoint inhibitor EN CAR T cells diffuse large B cell lymphoma immune checkpoint inhibitor 217 218 2 07/14/23 20230715 NES 230715 Exhaustion describes a condition in which T cells are unable to perform any function. A second expansion of circulating CAR T cells was observed, after a single injection of nivolumab, which argues on reversion of CAR T cell exhaustion: C SB max sb was 0.035 G/L, lower that the initial expansion but following a long period when the CAR T cells were undetectable. [Extracted from the article]