AbstractPurpose: This study aimed to explore metabolic tumor volume (MTV) as assessed by 18F-fluorodeoxyglucose positron emission tomography–computed tomography (18F-FDG–PET/CT) and understand its biological meaning in patients with non–small cell lung cancer (NSCLC) exposed to immune checkpoint blockers (ICB). Experimental Design: In this study, patients with advanced NSCLC and a positive PET scan within 42 days of first-line treatment were enrolled in 11 institutions across four countries. Total MTV (tMTV) was analyzed, with a 42% maximum standardized uptake value threshold. Survival was analyzed according to high tMTV (≥median). Plasma proteomic profile, whole exome, transcriptome, and other analyses were performed on monocentric cohorts to explore its biological correlates. Results: Of the 518 patients included, 167 received ICBs, 257 had chemotherapy plus ICBs, and 94 had chemotherapy. Median tMTV was 99 cm3. Median overall survival (OS) for patients with high tMTV treated with ICBs was 11.4 vs. 29.6 months (P < 0.0012) for those with low tMTV. In patients who received chemotherapy–ICB, tMTV did not correlate with OS (P = 0.099). In patients with programmed death-ligand 1 (PD-L1) ≥1% and high tMTV, chemotherapy–ICB combination was associated with longer OS compared with ICBs alone (20 vs. 11.4 months; P = 0.026), while no survival differences were observed in the low tMTV group. High tMTV correlated (and its detrimental effect seems to be driven) with a specific proteomic profile and increase in genomic instability. Conclusions: Our analysis indicates high tMTV is linked to an increase in systemic inflammation, specific cytokines production, and chromosomal instability. tMTV may serve as one of the biomarkers to select the best upfront strategy in patients with PD-L1–positive advanced NSCLC.

Treatment and dose modifications in patients according to their DCB status.

Additional significant differences in circulating chemokines.

Cytotoxic response in tumor biopsies of patients with No DCB upon combination treatment.

Further descriptions of tumor immune infiltrates.

Adverse events emergent during treatment and related to experimental drugs by the investigators according to CTCAE Version 4.03.

Gating strategy for flow cytometry analyses of T cells infiltration on tumor biopsies.

Immuno-Histo-Chemistry scoring of baseline tumor biopsies according to their DCB status.

Differential Gene Expression (DGE) of baseline tumor biopsies between patients with DCB and No DCB.

Baseline characteristics of the patients treated.

Chemotherapy associated with Immune Checkpoint Inhibitors is currently the standard of care in several tumor indications. This combination approach improves progression free survival (PFS), overall survival (OS) and complete pathological response (pCR) in several cancer types both in the early and metastatic approaches. However, the distinct spectrum of toxicities between cytotoxic side effects and immune related adverse events (irAEs) with similar clinical presentations and different management strategies remains a challenge in daily practice for healthcare professionals. This review summarizes the most common toxicities reported in the randomized clinical trials that led to the subsequent FDA approval of these combinations, across tumor indications. We cite in particular: non-small cell lung cancer, small cell lung cancer, triple negative breast cancer, squamous cell carcinoma of the head and neck, gastric carcinoma, esophageal carcinoma, cervical carcinoma and biliary tract carcinoma. We found that the combination of chemotherapy and immunotherapy was associated with an increased incidence of all grade adverse events (RR 1.11 [1.09; 1.12]) without an excess in treatment related mortality when compared to chemotherapy alone. We report also an increase in the incidence of serious adverse events (grade ≥ 3) (RR 1.16 [1.10;1.24]); in particular: high grade diarrhea, dyspnea, fatigue, rash and elevated liver enzymes. Together with the collaboration of our institutional network of organ specialists with expertise in irAEs, we propose practical recommendations for physicians to enhance clinical care and management of patients undergoing treatment with combined ICI immunotherapy and chemotherapy.

Autoimmune hemolytic anemia (AIHA) is defined as augmented destruction of erythrocytes by autoimmune mechanisms, usually mediated by autoantibodies against erythrocyte surface antigens.1 Drug-induced hemolytic anemia is distinct cause of AIHA and is generally mediated by immunological mechanisms.1 Immune checkpoint inhibitors (ICIs) that are used to treat cancer, in particular PD-1 inhibitors, can induce AIHA.1, 2 The hematopoietic system and red blood cells could be occasionally involved as immune-related adverse events triggered by ICI with a frequency estimated to be around 0.5% of treated patients.3 ICI-AIHAs have only been reported in few patients in cases-series,2, 3 and data remain scarce about AIHA subtype distributions (warm vs. cold) and outcome of patients including mortality associated with AIHA and treatment efficacy. Management of patients with ICI-AIHA is based on corticosteroids and eventually rituximab,2, 3 and safety and efficacy data are not fully reported. We report here the management and therapeutic outcome of patients treated for ICI-AIHA in a tertiary academic anticancer center. The study design was an observational retrospective study of adult patients with ICI-AIHA in France. Immune checkpoint inhibitors considered for the study included anti-programmed death cell 1 (PD-1), anti-programmed death cell ligand 1 (PD-L1), and anti-CTLA4. Eligibility criteria were patients aged ≥18 years, with ICI-AIHA who were registered in the pharmacovigilance registry REISAMIC (Registry of Severe Adverse Reactions to Immunomodulatory Monoclonal Antibodies in Cancer)4 and those referred to the Gustave Roussy Immunotoxicity board5 over the period from June 27, 2014, to April 29, 2022, and those referred to the centers belonging to the French Reference Centers for Adult' Autoimmune Cytopenias (CeReCAI) network from 2014 to 2022 (Figure 1). The AIHA criteria and definitions for this study followed the 2020 first international consensus criteria for AIHA management.6 Study objectives, data collection information, statistical analysis, and ethical considerations are detailed in the Appendix S1. Between June 27, 2014, and April 29, 2022, 21 patients with confirmed ICI-AIHA were included in analysis (Figure 1). Among 2775 patients prospectively included in the REISAMIC registry of Gustave Roussy Centre, two patients have developed ICI-AIHA, and the rate of ICI-AIHA was 0.07% (two out of 2775 ICI-treated patients). Among the 21 patients diagnosed with ICI-AIHA; median age at onset of ICI-AIHA was 70 years (ranging from 29 to 88 years); sex ratio was 2.0 (14 men and 7 women); and tumor types were non-small cell lung carcinoma (n = 8; 38%), melanoma (n = 7; 33%), renal cancer (n = 3; 14%), Hodgkin lymphoma (n = 1; 5%), and other tumor types (n = 2; 10%). Patients with ICI-AIHA mostly received anti-PD-1 immunotherapy (n = 17; 81% of cases) and developed ICI-AIHA after a median time of 28 days (ranging from 11 to 1060 days) (Table S1). A medical history of lymphoproliferative disorder was found in 9/21 patients (43%), and a pre-existing autoimmune or inflammatory disease was known for three patients (14%). The lymphoproliferative disorders were chronic lymphocytic leukemia (n = 3 patients), marginal zone lymphoma (n = 2 patients), Hodgkin lymphoma (n = 2 patients), Waldenstrom disease (n = 1 patient), and monoclonal gammopathy of undetermined significance (n = 1 patient) (Table S1). Among these nine patients with lymphoproliferative disorder, only one patient had a previously known lymphoproliferative disorder (patient with Hodgkin lymphoma, treated with anti-PD1), the other eight patients had no known history of lymphoproliferative disorder, and the diagnosis of lymphoproliferative disorder was performed and revealed at the same time of ICI-AIHA. Nadir of hemoglobin was 6.9 g/dL (range 4.2–9.6 g/dL), and 14 patients (71%) required red blood cell transfusions for anemia management, with a median of four packed red cell units per patient (range 1–8). Mortality related to ICI-AIHA was observed in two (10%) patients (Table S2). According to common terminology criteria for adverse events (CTCAEV5), severity of anemia was grade ≥3 in 18 (86%) patients, and the severity of anemia was observed and distributed according to each ICI-AIHA subtype (Figure 1). All patients had direct antiglobulin test (DAT) performed, and 19 (90%) had a positive test, with an IgG pattern for 11 (52%) and qualified as warm ICI-AIHA, five (24%) were positive for IgM and qualified as cold ICI-AIHA, and three (14%) had a mixed profile and qualified as mixed ICI-AIHA. Two patients (10%) had a negative DAT (Table S1). Fourteen (66%) patients received corticosteroids alone, and six (29%) patients received corticosteroids and rituximab (Tables S2 and S3). One patient received only palliative therapies without specific treatment for ICI-AIHA and died due to cancer progression before receiving any specific treatment for ICI-AIHA. Overall complete response to corticosteroids was 36% (5/14 patients treated) (Table S2). The efficacy of corticosteroids was observed only in the warm-AIHA subtype (details of therapeutic responses by subtypes of ICI-AIHA are available in Tables S2 and S4). Six (29%) patients received rituximab for ICI-AIHA. The response rate to rituximab was 50% (3/6 patients treated) (Table S2). The efficacy of rituximab was 1/3 and 2/2 of treated patients in the warm-AIHA and cold-AIHA subtypes, respectively. Remission of ICI-AIHA was achieved in 19 of the 21 patients (90%), and treatment outcomes were complete response in eight (38%) patients and partial response in 11 (52%) patients, with similar response rates among patients treated with corticosteroids or with corticosteroids plus rituximab (Table S2). Evolution of hemoglobin after ICI-AIHA treatments according to corticosteroid or corticosteroid plus rituximab was similar as depicted in Figure 1. Although hemoglobin concentration at ICI-AIHA diagnosis timepoints tended to be lower in patients treated with corticosteroids plus rituximab as compared to corticosteroids alone (Hb 5.8 g/dL vs. 7.3 g/dL; p = .10; Table S3), the hemoglobin recovery at 6 months was similar (Figure 1). After ICI-AIHA diagnosis, immune checkpoint inhibitor therapy was permanently discontinued in 19 patients (90%). Two (9.5%) of the 21 patients were rechallenged with same ICI after obtaining durable complete remission of ICI-AIHA (Table S2). The two rechallenged patients were treated with corticosteroids alone, and in these two patients, no recurrence of ICI-AIHA was observed with a period after ICI rechallenge of 24 months. Finally, our study reports a case series of 21 patients diagnosed with ICI-AIHA delineating the subtypes of ICI-AIHA that appears to be mainly warm-AIHA (52%) and cold-AIHA (24%). DAT-negative ICI-AIHA was reported in 10% of cases, which seems to confirm that ICI-AIHA could be more frequently associated with negative DAT (DAT-negative AIHA is thought to be present in <5% of patients in the setting of AIHA outside of ICI1). Leaf et al.2 reported in the ICI-AIHA case series from the USA a negative DAT rate of 28%. Our study was able to estimate that ICI-AIHA is a rare complication associated with immunotherapy with an incidence rate of 0.07%. The mortality associated with ICI-AIHA was 10% of patients in our study, which indicates that ICI-AIHA was a severe and potential life-threatening complication of immunotherapy. In all patients in the study, corticosteroids or corticosteroids plus rituximab produced similar results on hemoglobin recovery, with remission of ICI-AIHA in 90% of patients. Overall, our results indicate that ICI-AIHA treatment should consider the AIHA subtypes; warm ICI-AIHA is to be treated with corticosteroids, with addition of rituximab in cases of insufficient response to corticosteroids. In patients with cold ICI-AIHA, corticosteroids do not seem to be effective, and the treatment should be based on rituximab. In our study, ICI-AIHA was associated with an underlying lymphoproliferative disorder in 43% of patients. Leaf et al.,2 in another report of ICI-AIHA, found an associated lymphoproliferative syndrome (most often chronic lymphocytic leukemia or indolent lymphoma) in 29% of their patients. We could discuss the causal factor of AIHA between the immunotherapy treatment or the natural evolution of the underlying lymphoproliferative syndrome, or the conjunction of the two. In conclusion, main ICI-AIHA subtypes included both warm-AIHA and cold-AIHA. An associated underlying lymphoproliferative disorder was frequently observed and should be recommended to look for. Our study suggests that ICI-AIHA treatment should consider AIHA subtypes: corticosteroids ± rituximab for warm-AIHA and rituximab alone for cold-AIHA. Marion Plaçais, Jean-Marie Michot, and Olivier Lambotte contributed to conception and design. Olivier Lambotte, Sabine Messayke, Jean-Marie Michot, Kaissa Ouali, Thibault Comont, Nora Kramkimel, Alexandre Thibault Jacques Maria, Laetitia Coutte, Charlee Nardin, Guillaume Manson, Ariane Laparra, and Audrey Perret contributed to provision of study materials or patients. Marion Plaçais, Kaissa Ouali, and Jean-Marie Michot collected and assembled the data. Marion Plaçais, Jean-Marie Michot, Ariane Laparra, Marc Michel, and Olivier Lambotte helped in data analysis and interpretation. All authors wrote and approved the final version of the manuscript. Data were collected by investigators and site personnel and analyzed in collaboration with senior academic authors. We thank the patients and their families and all investigators and site personnel. The authors thank Tina-Marie Zaarour for his assistance with copyediting. We thank the CeReCAI (Centre de Référence des Cytopénies Auto-Immunes de l'adulte) and the sites belonging to the CeReCAI in France. JMM and KO disclosed conflicts of interest outside of the submitted work: Institution received funding for clinical trials, and they both were principal/sub-investigator of clinical trials for Abbvie, Agios, Amgen, Argen-x, Astex, AstraZeneca, Beigene, Blueprint, BMS, Boehringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Seattle Genetics, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, and Xencor. JMM reported advisory board for Ideogen and Gilead and for Mallinckrodt Pharmaceuticals, steering committee member for Regeneron, and expert testimony fees for MSD; travel grant was paid by GSK. NK reported disclosed conflicts of interest outside of the submitted work with consultancy fees for BMS, and travel grant was paid by BMS. CN disclosed conflicts of interest outside of the submitted work: CN reported consultancy fees for BMS, Novartis, and MSD. ATJM disclosed conflicts of interest outside of the submitted work: consultancy fees for BMS, Astra Zeneca, MSD, Roche, and Sanofi. OL disclosed conflicts of interest outside of the submitted work: OL reported expert testimony and consultancy fees from Bristol-Myers Squibb France, MSD, and AstraZeneca, consultancy fees from Boehringer, and expert testimony fees from Abbvie. The other authors declare they have no conflicts of interest related to this study. The authors declare that the data presented in this article are available as raw data available from the corresponding author upon reasonable request. Appendix S1. Supporting information. Table S1. Characteristics of patients with immunotherapy-induced autoimmune hemolytic anemia. Table S2. Therapies administered and outcome in patients with immunotherapy-induced autoimmune hemolytic anemia. Table S3. Clinical characteristics and outcome of patients, according to treatment administered for immunotherapy-induced autoimmune hemolytic anemia. Table S4. Complete response to treatment of immunotherapy-induced autoimmune hemolytic anemia, according to each anemia subtype. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Immunotherapy profoundly changed the landscape of cancer therapy by providing long-lasting responses in subsets of patients and is now the standard of care in several solid tumor types. However, immunotherapy activity beyond conventional immune checkpoint inhibition is plateauing, and biomarkers are overall lacking to guide treatment selection. Most studies have focused on T cell engagement and response, but there is a growing evidence that B cells may be key players in the establishment of an organized immune response, notably through tertiary lymphoid structures. Mechanisms of B cell response include antibody-dependent cellular cytotoxicity and phagocytosis, promotion of CD4+ and CD8+ T cell activation, maintenance of antitumor immune memory. In several solid tumor types, higher levels of B cells, specific B cell subpopulations, or the presence of tertiary lymphoid structures have been associated with improved outcomes on immune checkpoint inhibitors. The fate of B cell subpopulations may be widely influenced by the cytokine milieu, with versatile roles for B-specific cytokines B cell activating factor and B cell attracting chemokine-1/CXCL13, and a master regulatory role for IL-10. Roles of B cell-specific immune checkpoints such as TIM-1 are emerging and could represent potential therapeutic targets. Overall, the expanding field of B cells in solid tumors of holds promise for the improvement of current immunotherapy strategies and patient selection.

PURPOSE With liquid biopsy's widespread adoption in oncology, an increased number of clonal hematopoiesis–associated mutations (CHm) have been identified in patients with solid tumors. However, its impact on patient outcomes remains unclear. This study aimed to analyze and describe CHm in a cohort of phase I patients. METHODS Retrospective data collection from medical records and molecular profiles (Foundation One Liquid CDx Assay) was performed before first study drug administration at the Drug Development Department of Gustave Roussy (France) within the STING trial (ClinicalTrials.gov identifier: NCT04932525 ). CHm prevalence was assessed using any and ≥1% variant allele frequency (VAF) in epigenetic modifier genes ( DNMT3A, TET2, and ASXL1). RESULTS From January 2021 to December 2022, 255 patients were enrolled in a phase I clinical trial. A total of 55% were male, with a median age of 62 years (24-86). Principal tumor locations were GI (27%) and genitourinary (21%). Overall, 104 patients (41%) had at least one CHm in liquid biopsy, with 55 patients (22%) having a VAF of ≥ 1%. The most frequent mutation was DNMT3A 73% at any VAF (n = 76) and 22% at 1% VAF (n = 23). Median progression-free survival (PFS) and overall survival were 3.8 months (m) for the CHm group versus 3.2 m for nonclonal hematopoiesis (CH; P = .08) and 18.26 m CHm versus 15.8 m non-CH ( P = .9), respectively. PFS increased in the CHm population treated with targeted therapy (hazard ratio, 0.6 [95% CI, 0.42 to 0.84]; P = .004). CONCLUSION CHm was commonly found in patients with solid tumors treated in phase I trials, with a prevalence of 41% in our cohort. The most frequently mutated gene was DNMT3A. The presence of CHm had no impact on the population of patients treated in the phase I trials.

BACKGROUND:Potential associations between targeted therapies and a new cancer in patients with inflammatory arthritis (IA) and a previous malignancy are a frequent concern in daily rheumatology practice. OBJECTIVES:To develop points to consider (PTC) to assist rheumatologists when initiating a targeted therapy in the context of a previous malignancy. METHODS:Following EULAR standardised operating procedures, a task force met to define the research questions for a systematic literature review and to formulate the overarching principles (OPs) and the PTC. RESULTS:The group formulated five OPs; seven PTC were formulated concerning the initiation of targeted therapies in patients with active IA and a previous malignancy in remission and one PTC concerning patients with active IA who were not in cancer remission. Major themes included (a) the need to assess the individualised risk of cancer recurrence based on the characteristics of the patient, cancer and the underlying disease; (b) the importance of engaging with specialists caring for cancer and defining treatment based on a shared decision between the patient and the rheumatologist; (c) the value of initiating without delay an appropriate targeted therapy for the treatment of the IA in patients in remission of their cancer; (d) the proposal to use Janus kinase inhibitors and abatacept with caution and in the absence of therapeutic alternatives, based on the absence of any data concerning their use in the context of previous malignancy. CONCLUSION:The 2024 EULAR points to consider provide guidance on the management of targeted therapies in patients with IA and a previous malignancy.

Antibody–drug conjugates (ADCs) offer a promising path for cancer therapy, leveraging the specificity of monoclonal antibodies and the cytotoxicity of linked drugs. The success of ADCs hinges on precise targeting of cancer cells based on protein expression levels. This review explores the relationship between target protein expression and ADC efficacy in solid tumours, focusing on results of clinical trials conducted between January 2019 and May 2023. We hereby highlight approved ADCs, revealing their effectiveness even in low-expressing target populations. Assessing target expression poses challenges, owing to variations in scoring systems and biopsy types. Emerging methods, like digital image analysis, aim to standardize assessment. The complexity of ADC pharmacokinetics, tumour dynamics, and off-target effects emphasises the need for a balanced approach. This review underscores the importance of understanding target protein dynamics and promoting standardized evaluation methods in shaping the future of ADC-based cancer therapies.

IntroductionImmune checkpoint blockers (ICBs) revolutionized the treatment of patients with advanced non-small cell lung cancer (NSCLC) but only a fraction of them obtain a response, and clinical benefit from these treatments is often difficult to predict. The aim of our study is to unveil the potential implications of antibody response to previous viral infections in predicting response to ICBs in patients with NSCLC.MethodsSera from patients treated with ICBs alone, chemotherapy (CT) or a combination of CT-ICBs were analyzed with VirScan (CDI Labs, USA), a high-throughput method that comprehensively analyzes epitope-level antiviral IgG antibodies via programmable phage display and immunoprecipitation sequencing.Total number of unique positive peptides (tUP) was defined as the total number of non-overlapping positive “is a hit” peptides for each patient.ResultsOverall, 387 patients were included. Of them, 129 were treated with ICBs alone, 66 with CT-ICBs and 195 with CT alone. 90 out of 129 patients treated with ICBs alone received ICBs as a subsequent line of treatment, while CT-ICBs and CT were administered as upfront therapies.A higher tUP was correlated with improved overall survival in patients treated with ICBs, and confirmed in the multivariate model (HR 0.43, 95% CI 0.24, 0.79, p=0.006), while it was not in those treated with CT-ICBs (p=0.8) and CT alone (p=0.1).tUP was not correlated with programmed death-ligand 1 (PD-L1) expression, while at the transcriptome level it was correlated with several immune-related pathways, particularly involving B cells.ConclusionA higher number of viral peptides recognized by serum antibodies might reflect increased immune fitness, resulting in improved outcomes in ICBs treated patients with NSCLC.

BACKGROUND:Targeted therapies have been associated with potential risk of malignancy, which is a common concern in daily rheumatology practice in patients with inflammatory arthritis (IA) and a history of cancer. OBJECTIVES:To perform a systematic literature review to inform a Task Force formulating EULAR points to consider on the initiation of targeted therapies in patients with IA and a history of cancer. METHODS:Specific research questions were defined within the Task Force before formulating the exact research queries with a librarian. We included studies reporting a relative risk measure of patients with a history of cancer initiating a targeted therapy or a conventional synthetic disease-modifying antirheumatic drug (csDMARD), regardless of the time since diagnosis of cancer. All relevant studies included in PubMed or Embase up to 15 July 2022 were included. Two reviewers independently performed standardised article selection, data extraction, synthesis and risk of bias assessment. RESULTS:14 published articles and one ACR abstract fulfilled the inclusion criteria. All studies were high-quality observational studies, representing a median follow-up from treatment initiation of 4.52 years among 4428 patients and 15 062 patient-years of follow-up for new or recurrent cancer. All patients had a history of cancer, most frequently solid cancer, most frequently receiving treatment for rheumatoid arthritis and most frequently treated with tumour necrosis factor-alpha inhibitors. Across these studies, the overall HR of new incident cancer or cancer recurrence was 0.90 (95% CI 0.74 to 1.10) for patients receiving a targeted therapy versus a csDMARD. CONCLUSION:Overall, the targeted therapies and clinical contexts covered by the included studies were not associated with an increased risk of new incident cancer or cancer recurrence as compared with csDMARDs.

A case series evaluating efficacy and safety of immune checkpoint blockade in Li-Fraumeni syndrome