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B-cell acute lymphoblastic leukemia (B-ALL) is the most common subtype of acute leukemia in the pediatric population. The prognosis and treatment of B-ALL have dramatically improved over the past decade with the adoption of intensive and prolonged combination chemotherapy regimens. The advent of novel immunologic agents such as blinatumomab and inotuzumab has changed the treatment landscape of B-ALL. However, patients have continued to relapse, raising the need for novel therapies. Chimeric antigen receptor (CAR) T-cells have achieved a milestone in the treatment of B-ALL. Two CD19-targeting CAR T-cells were approved by the Food and Drug Administration and the European Medicines Agency for the treatment of relapsed and/or refractory B-ALL. In this review, we review the available data regarding CD19-targeting CAR T-cells with their safety profile as well as the mechanism of resistance to these agents and the way to overcome this resistance. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 pandemic still represents a threat for immunosuppressed and hematological malignancy (HM) bearing patients, causing increased morbidity and mortality. Given the low anti-SARSCoV-2 IgG titers post-vaccination, the COVID-19 threat prompted the prophylactic use of engineered anti-SARS-CoV-2 monoclonal antibodies. In addition, potential clinical significance of T cell responses has been overlooked during the first waves of the pandemic, calling for additional in-depth studies. We reported that the polarity and the repertoire of T cell immune responses govern the susceptibility to SARS-CoV-2 infection in health care workers and solid cancer patients. Here, we longitudinally analyzed humoral and cellular immune responses at each BNT162b2 mRNA vaccine injection in 47 HM patients under therapy. Only one-third of HM, mostly multiple myeloma (MM) bearing patients, could mount S1-RBD-specific IgG responses following BNT162b2 mRNA vaccines. This vaccine elicited a S1-RBD-specific Th1 immune response in about 20% patients, mostly in MM and Hodgkin lymphoma, while exacerbating Th2 responses in the 10% cases that presented this recognition pattern at baseline (mostly rituximab-treated patients). Performing a third booster barely improved the percentage of patients developing an S1-RBD-specific Th1 immunity and failed to seroconvert additional HM patients. Finally, 16 patients were infected with SARS-CoV-2, of whom 6 developed a severe infection. Only S1-RBD-specific Th1 responses were associated with protection against SARS-CoV2 infection, while Th2 responses or anti-S1-RBD IgG titers failed to correlate with protection. These findings herald the paramount relevance of vaccine-induced Th1 immune responses in hematological malignancies. [ABSTRACT FROM AUTHOR]

Introduction: Primary mediastinal large B-cell lymphoma (PMBL) is a rare subtype of lymphoma, clinically and biologically distinct from diffuse large B-cell lymphoma (DLBCL) that shows overlapping features with classical Hodgkin lymphoma (cHL). If first-line strategies lead to 80–85% of curability, relapse occurs early with a chemo-refractory disease and a poor outcome. The presence of 9p24.1 rearrangement, conducting to the overexpression of the immune checkpoint molecules PDL1 and 2, has paved the way for immune checkpoint blockers development in these entities. Pembrolizumab, an anti PD-1 checkpoint antibody, was initially approved in solid cancer and later on in the lymphoma field in cHL. Areas covered: We summarize the biology and clinical need in PMBL, leading to the rationale for checkpoint inhibitors development, as well as pembrolizumab clinical studies in this entity. To do so, we performed a PubMed search using the terms: 'PMBCL,' 'lymphoma,' 'Immune checkpoint,' and 'Pembrolizumab.' Expert opinion: Pembrolizumab showed tolerable safety profile and efficacy data in patients with PMBL who have relapsed after, or are ineligible for autologous stem cell transplant (ASCT). Some combination strategies have shown promising preliminary results, while others are currently being conducted. [ABSTRACT FROM AUTHOR]

Summary: Lymphoma‐associated haemophagocytic syndrome (LAHS) accounts for most cases of secondary haemophagocytic syndrome (HS) and has been extensively described in Asian populations. However, little is known about the epidemiology of LAHS in Western countries. We herein report a case series of 71 LAHS patients in which the lymphomas were mainly of the aggressive type. Diagnoses included non‐Hodgkin B cell lymphoma (46·5%) including human herpes virus 8‐associated non‐Hodgkin lymphoma (12·7%), T cell lymphoma (28·2%) and Hodgkin lymphoma (23·9%). An underlying immunodeficiency was described in 30 patients (42·3%). Early mortality within the 30 days following HS diagnosis was observed in 26·8% of cases. The overall survival was estimated at 45·7% [95% confidence interval, CI (35·4–59·0)] at 6 months, and 34·3% [95% CI (24·8–47·4)] at 2 years. Concurrent infection, age over 50 years, ethnicity and etoposide treatment were independently associated with mortality. While it appears that certain types of lymphomas were more prone to trigger HS, LAHS were not restricted to a few types of lymphoma. The overall prognosis was poor, with a particularly high rate of early mortality, highlighting the importance of both early recognition and choice of initial therapeutic management. [ABSTRACT FROM AUTHOR]

Background Although safety and prognostic factors for overall survival (OS) have been extensively studied in Phase I clinical trials on patients with solid tumours, data on lymphoma trials are scarce. Here, we investigated safety, outcomes and prognostic factors in relapsed or refractory lymphoma patients included in a series of Phase I trials. Method and patients All consecutive adult patients with recurrent/refractory lymphoma enrolled in 26 Phase I trials at a single cancer centre in France between January 2008 and June 2016 were retrospectively assessed. Results 133 patients (males: 65%) were included in the analysis. The median (range) age was 65 (23–86). Aggressive non-Hodgkin, indolent non-Hodgkin and Hodgkin types accounted for 64%, 25% and 11% of the patients, respectively. The patients had received a median (range) of 3 (1–13) lines of treatment prior to trial entry. The median [95% confidence interval] progression-free survival and OS times were 3.0 [1.8–3.6] and 17.8 [12.7–30.4] months, respectively. High-grade toxicity (grade 3 or higher, according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events classification) was experienced by 56 of the 133 patients (42%) and was related to the investigational drug in 44 of these cases (79%). No toxicity-related deaths occurred. Dose-limiting toxicity (DLT) was encountered in 11 (9%) of the 116 evaluable patients. High-grade toxicity occurred during the DLT period for 34 of the 56 patients (61%) and after the DLT period in the remaining 22 (39%). The main prognostic factors for poor OS were the histological type (i.e. tumour aggressiveness), an elevated serum LDH level, and a low serum albumin level. Early withdrawal from a trial was correlated with the performance status score, the histological type and the serum LDH level. The overall objective response and disease control rates were 24% and 57%, respectively. Conclusion Performance status, LDH, albumin and histological type (tumour aggressiveness) appear to be the most relevant prognostic factors for enrolling Phase I participants with relapsed or refractory lymphoma. 39% of the patients experienced a first high-grade toxic event after the dose-limiting toxicity period, suggesting that the conventional concept of dose-limiting toxicity (designed for chemotherapy) should be redefined in the era of modern cancer therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint blockers are important immunotherapies for the treatment of patients with Hodgkin lymphoma. The resistance mechanisms of these immunotherapies remain unknown. This pilot study aims to decipher the resistance mechanisms of immunotherapies in Hodgkin lymphoma. The main results show that immunotherapy-resistant Hodgkin lymphoma had CD8 lymphocytes depleted in microenvironment and overexpression of the LAG-3 molecule. This study proposes hypotheses for understanding the resistance to immunotherapies in patients with Hodgkin lymphoma. Background: Resistance to anti-PD-1 remains a considerable clinical challenge for the treatment of patients with classical Hodgkin lymphoma (cHL), and mechanisms of anti-PD-1 resistance remain unknown. This pilot study aims to investigate the tumor microenvironment in patients with cHL relapsing after anti-PD-1. Methods: This study investigated tumor samples of eight patients with cHL, including four patients exposed to anti-PD-1 with a paired longitudinal histological analysis before and after anti-PD-1, and four patients not exposed to anti-PD-1 who served as control for the cellular biological investigations. Fresh cells tumor microenvironment analysis included phenotypic characterization of their T cell surfaces immune checkpoint markers PD-1, PD-L1, ICOS, TIM-3, LAG-3, 41-BB and BTLA. Tumor tissues immunohistochemistry staining included CD30, CD4, CD8, CD68, CD163, PD-L1, PD-1, LAG-3 and TIM-3. Findings: Paired longitudinal tumor tissues analysis in the tumor microenvironment found a CD8+ lymphocytes tumor depletion and an increase of LAG-3 staining after anti-PD-1 exposure. The fresh cells analysis of the tumor microenvironment in patients exposed to anti-PD-1 found CD8+ lymphocyte depletion, with an elevated CD4+/CD8+ lymphocytes ratio (median ratio 9.77 in exposed anti-PD-1 versus 2.39 in not-exposed anti-PD-1 patients; p = 0.0943). On the cell surfaces of CD4+ lymphocytes, the median positive expression of LAG-3 was significantly higher in the samples exposed to anti-PD-1 compared to the controls (15.05 [IQR:17.91–10.65] versus 3.84 [IQR 1.87–6.57]; p = 0.0376). Interpretation: This pilot study proposes hypotheses for understanding the resistance to immunotherapies in patients with Hodgkin lymphoma. Hodgkin lymphoma exposed to anti-PD-1 correlated in tumor microenvironment with an immune depletion of CD8+ T lymphocytes and overexpression of LAG-3 on CD4+ helper T lymphocytes. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases (ND) are characterized by progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood, hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing mitogen-activated protein kinase (MAPK)-activating mutations that differentiate into senescent myeloid cells that drive lesion formation. Some individuals with LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we showed that LCH-ND was caused by myeloid cells that were clonal with peripheral LCH cells. Circulating BRAF V600E+ myeloid cells caused the breakdown of the blood-brain barrier (BBB), enhancing migration into the brain parenchyma where they differentiated into senescent, inflammatory CD11a+ macrophages that accumulated in the brainstem and cerebellum. Blocking MAPK activity and senescence programs reduced peripheral inflammation, brain parenchymal infiltration, neuroinflammation, neuronal damage and improved neurological outcome in preclinical LCH-ND. MAPK activation and senescence programs in circulating myeloid cells represent targetable mechanisms of LCH-ND. [Display omitted] • MAPK activation in BM-derived CD11a+ macrophages drives neurodegeneration in LCH mice • Similar spatial and transcriptional patterns between mouse and human CNS LCH • LCH mice have a leaky BBB and enhanced CNS inflammation • Senolytic treatment prevents neurodegenerative phenotype in LCH mice Patients with Langerhans cell histiocytosis can develop incurable neurodegeneration years after initial systemic disease. Wilk et al. found that MAPK activation in circulating myeloid cells drives a senescent and proinflammatory state that contributes to breakdown of the blood-brain barrier and accumulation of mutant macrophages in the brain. Cognitive and motor deficits can be prevented by MAPK and senolytic Bcl-xL-inhibition. [ABSTRACT FROM AUTHOR]

Summary To guide the design of immunotherapy strategies for patients with early stage lung tumors, we developed a multiscale immune profiling strategy to map the immune landscape of early lung adenocarcinoma lesions to search for tumor-driven immune changes. Utilizing a barcoding method that allows a simultaneous single-cell analysis of the tumor, non-involved lung, and blood cells, we provide a detailed immune cell atlas of early lung tumors. We show that stage I lung adenocarcinoma lesions already harbor significantly altered T cell and NK cell compartments. Moreover, we identified changes in tumor-infiltrating myeloid cell (TIM) subsets that likely compromise anti-tumor T cell immunity. Paired single-cell analyses thus offer valuable knowledge of tumor-driven immune changes, providing a powerful tool for the rational design of immune therapies. Video Abstract [ABSTRACT FROM AUTHOR]

We developed a phenotypic screening platform for the functional exploration of dendritic cells (DC). Here, we report a genome-wide CRISPR screen that revealed BCL2 as an endogenous inhibitor of DC function. Knockout of BCL2 enhanced DC antigen presentation and activation as well as the capacity of DCs to control tumors and to synergize with PD-1 blockade. The pharmacologic BCL2 inhibitors venetoclax and navitoclax phenocopied these effects and caused a cDC1-dependent regression of orthotopic lung cancers and fibrosarcomas. Thus, solid tumors failed to respond to BCL2 inhibition in mice constitutively devoid of cDC1, and this was reversed by the infusion of DCs. Moreover, cDC1 depletion reduced the therapeutic efficacy of BCL2 inhibitors alone or in combination with PD-1 blockade and treatment with venetoclax caused cDC1 activation, both in mice and in patients. In conclusion, genetic and pharmacologic BCL2 inhibition unveils a DC-specific immune checkpoint that restrains tumor immunosurveillance., Significance: BCL2 inhibition improves the capacity of DCs to stimulate anticancer immunity and restrain cancer growth in an immunocompetent context but not in mice lacking cDC1 or mature T cells. This study indicates that BCL2 blockade can be used to sensitize solid cancers to PD-1/PD-L1-targeting immunotherapy. This article is featured in Selected Articles from This Issue, p. 2293., (©2023 American Association for Cancer Research.)

Vaccination against coronavirus disease 2019 (COVID-19) relies on the in-depth understanding of protective immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We characterized the polarity and specificity of memory T cells directed against SARS-CoV-2 viral lysates and peptides to determine correlates with spontaneous, virus-elicited, or vaccine-induced protection against COVID-19 in disease-free and cancer-bearing individuals. A disbalance between type 1 and 2 cytokine release was associated with high susceptibility to COVID-19. Individuals susceptible to infection exhibited a specific deficit in the T helper 1/T cytotoxic 1 (Th1/Tc1) peptide repertoire affecting the receptor binding domain of the spike protein (S1-RBD), a hotspot of viral mutations. Current vaccines triggered Th1/Tc1 responses in only a fraction of all subject categories, more effectively against the original sequence of S1-RBD than that from viral variants. We speculate that the next generation of vaccines should elicit Th1/Tc1 T-cell responses against the S1-RBD domain of emerging viral variants., Significance: This study prospectively analyzed virus-specific T-cell correlates of protection against COVID-19 in healthy and cancer-bearing individuals. A disbalance between Th1/Th2 recall responses conferred susceptibility to COVID-19 in both populations, coinciding with selective defects in Th1 recognition of the receptor binding domain of spike. See related commentary by McGary and Vardhana, p. 892. This article is highlighted in the In This Issue feature, p. 873., (©2022 The Authors; Published by the American Association for Cancer Research.)

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with persistent MAPK pathway activation. Standard-of-care chemotherapies are inadequate for most patients with multisystem disease, and optimal strategies for relapsed and refractory disease are not defined. The mechanisms underlying development of inflammation in LCH lesions, the role of inflammation in pathogenesis, and the potential for immunotherapy are unknown. Analysis of the immune infiltrate in LCH lesions identified the most prominent immune cells as T lymphocytes. Both CD8+ and CD4+ T cells exhibited "exhausted" phenotypes with high expression of the immune checkpoint receptors. LCH DCs showed robust expression of ligands to checkpoint receptors. Intralesional CD8+ T cells showed blunted expression of Tc1/Tc2 cytokines and impaired effector function. In contrast, intralesional regulatory T cells demonstrated intact suppressive activity. Treatment of BRAFV600ECD11c LCH mice with anti-PD-1 or MAPK inhibitor reduced lesion size, but with distinct responses. Whereas MAPK inhibitor treatment resulted in reduction of the myeloid compartment, anti-PD-1 treatment was associated with reduction in the lymphoid compartment. Notably, combined treatment with MAPK inhibitor and anti-PD-1 significantly decreased both CD8+ T cells and myeloid LCH cells in a synergistic fashion. These results are consistent with a model that MAPK hyperactivation in myeloid LCH cells drives recruitment of functionally exhausted T cells within the LCH microenvironment, and they highlight combined MAPK and checkpoint inhibition as a potential therapeutic strategy., (© 2021 by The American Society of Hematology.)

Aim: Anti-CD20 monoclonal antibody is a cornerstone therapy for follicular lymphoma. Following anti-CD20 therapy, a potential decrease in CD20 antigen, and therefore a loss of the tumor target might be expected. However, the incidence and clinical significance of CD20 loss on tumor cells in patients with relapsed or refractory follicular lymphoma are unknown. This study aims to investigate the incidence and outcome of patients with relapsed or refractory follicular lymphoma patients harboring the loss of the tumor target, CD20. Methods: All consecutive adult patients with relapsed or refractory follicular lymphoma referred to the Early Drug Department at Gustave Roussy were included. The main objectives were to assess the incidence and prognosis of the loss in expression of CD20 antigen on the surface of tumor cells on patient outcome. Results: Over the study period 2013-2018, 131 patients were screened for clinical trials with B-cell malignancies in the early drug department of Gustave Roussy in France. Forty-four patients presented with relapsed or refractory follicular lymphoma and 32 had tumor biopsies at the time of relapse that were retained for analysis. The median (range) age was 67.5 years (55.3-75.3) and the median number of prior anti-cancer systemic therapies was 3 (2-4). At the time of relapse, CD20 expression was positive in 84% of tumors ( n = 27) and negative in 16% of tumors ( n = 5). At a median follow-up of 18.3 (0.6-83.3) months, CD20 negativity was associated with a poorer prognosis with a median overall survival of 8.9 months (95%CI: 2.4-19.1) in comparison to CD20 positive patients (28.3 months, 95%CI: 25.1-75.3 months, P = 0.019). Conclusion: The loss of the tumor target antigen, CD20, occurred in 16% of patients with relapse or refractory follicular lymphoma. Due to confounding factors in patients who received anti-CD20 immunotherapy, it was not possible to formally establish the prognostic significance of CD20 negativity. However, we suggest that a check for CD20 antigen positivity nevertheless be performed to adapt subsequent therapies for patients with relapsed or refractory follicular lymphoma., Competing Interests: Dr. Jean-Marie Michot, Vincent Ribrag, Clémentine Sarkozy and Christophe Massard declared as potential conflict of interest research fundings for their institutions as principal or sub-Investigator of Clinical Trials for the following compagnies: Abbvie, Agios, Amgen, Argen-x, Astex, AstraZeneca, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Genentech, Janssen, Kyowa, Lilly, Lysarc, Lytix Biopharma, Medimmune, Roche, Sanofi, Xencor. The other authors declared that there are no conflicts of interest with the presented manuscript., (© The Author(s) 2021.)

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207 + dendritic cells (DCs) with constitutively activated mitogen-activated protein kinase (MAPK) pathway signaling. Approximately 60% of LCH patients harbor somatic BRAF V600E mutations localizing to CD207 + DCs within lesions. However, the mechanisms driving BRAF V600E + LCH cell accumulation in lesions remain unknown. Here we show that sustained extracellular signal-related kinase activity induced by BRAF V600E inhibits C-C motif chemokine receptor 7 (CCR7)-mediated DC migration, trapping DCs in tissue lesions. Additionally, BRAF V600E increases expression of BCL2-like protein 1 (BCL2L1) in DCs, resulting in resistance to apoptosis. Pharmacological MAPK inhibition restores migration and apoptosis potential in a mouse LCH model, as well as in primary human LCH cells. We also demonstrate that MEK inhibitor-loaded nanoparticles have the capacity to concentrate drug delivery to phagocytic cells, significantly reducing off-target toxicity. Collectively, our results indicate that MAPK tightly suppresses DC migration and augments DC survival, rendering DCs in LCH lesions trapped and resistant to cell death., (© 2018 Hogstad et al.)

Background: Adolescent and young adults (AYA) represent one third of patients affected by Hodgkin lymphoma (HL). These patients are frequently treated either with pediatric or adult protocol depending on their physician background. This population has been understudied so far, in terms of HL characteristics and treatment-associated outcomes., Aim: We aimed to extensively describe HL features in the AYA population including HL characteristics, progression-free (PFS) and overall survival (OS)., Methods: From 1979 to 2013, consecutive patients with HL aged between 15 to 25 years and followed at Saint-Louis Hospital were prospectively enrolled. Survivals were estimated using the Kaplan-Meier method., Results: 349 patients were included and studied, with a median follow-up of 7 years. The majority of patients were treated with adult protocols (mainly ABVD and BEACOPP). They presented adverse clinical characteristics with a high proportion of stage III and IV according to Ann Arbor classification (45 %), a high rate of B symptoms (46 %) and extra-nodal involvement (36 %). Despite these pejorative clinical features, the prognosis remains good with a 10-year PFS and OS estimated at 81.0 % (95%CI [76.7-85.5]) and 90.7% (95%CI [87.2-94.4]), respectively. In multivariate analysis, stages III and IV according to Ann Arbor classification, mixed cellularity histology, elevated neutrophils and LDH above range were independently associated with a worse PFS. We identified a subgroup of 11 primary refractory patients with a particularly poor prognosis. The toxicity rate was low (7.4 %)., Conclusion: Despite their baseline pejorative features, AYA with HL have a good prognosis. Progresses are still needed in order to reduce toxicities. Primary refractory patients with a particularly poor prognosis should be detected early in order to quickly introduce new targeted therapies., Competing Interests: CONFLICTS OF INTEREST The authors declared no conflicts of interest related to this work.