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Background BCMA-directed CAR T-cell therapy (CAR-T) has altered the treatment landscape of relapsed/refractory (r/r) multiple myeloma, but is hampered by unique side effects that can lengthen hospital stays and increase morbidity. Hematological toxicity (e.g. profound and prolonged cytopenias) represents the most common grade ≥ 3 toxicity and can predispose for severe infectious complications. Here, we examined the utility of the CAR-HEMATOTOX (HT) score to predict toxicity and survival outcomes in patients receiving standard-of-care idecabtagene vicleucel and ciltacabtagene autoleucel. Methods Data were retrospectively collected from 113 r/r multiple myeloma patients treated between April 2021 and July 2022 across six international CAR-T centers. The HT score—composed of factors related to hematopoietic reserve and baseline inflammatory state—was determined prior to lymphodepleting chemotherapy. Results At lymphodepletion, 63 patients were HT low (score 0–1) and 50 patients were HT high (score ≥ 2). Compared to their HT low counterparts, HT high patients displayed prolonged severe neutropenia (median 9 vs. 3 days, p < 0.001), an increased severe infection rate (40% vs. 5%, p < 0.001), and more severe ICANS (grade ≥ 3: 16% vs. 0%, p < 0.001). One-year non-relapse mortality was higher in the HT high group (13% vs. 2%, p = 0.019) and was predominantly attributable to fatal infections. Response rates according to IMWG criteria were higher in HT low patients (≥ VGPR: 70% vs. 44%, p = 0.01). Conversely, HT high patients exhibited inferior progression-free (median 5 vs. 15 months, p < 0.001) and overall survival (median 10.5 months vs. not reached, p < 0.001). Conclusions These data highlight the prognostic utility of the CAR-HEMATOTOX score for both toxicity and treatment response in multiple myeloma patients receiving BCMA-directed CAR-T. The score may guide toxicity management (e.g. anti-infective prophylaxis, early G-CSF, stem cell boost) and help to identify suitable CAR-T candidates.

BackgroundCD19-directed chimeric antigen receptor T-cell therapy (CAR-T) represents a promising treatment modality for an increasing number of B-cell malignancies. However, prolonged cytopenias and infections substantially contribute to the toxicity burden of CAR-T. The recently developed CAR-HEMATOTOX (HT) score—composed of five pre-lymphodepletion variables (eg, absolute neutrophil count, platelet count, hemoglobin, C-reactive protein, ferritin)—enables risk stratification of hematological toxicity.MethodsIn this multicenter retrospective analysis, we characterized early infection events (days 0–90) and clinical outcomes in 248 patients receiving standard-of-care CD19 CAR-T for relapsed/refractory large B-cell lymphoma. This included a derivation cohort (cohort A, 179 patients) and a second independent validation cohort (cohort B, 69 patients). Cumulative incidence curves were calculated for all-grade, grade ≥3, and specific infection subtypes. Clinical outcomes were studied via Kaplan-Meier estimates.ResultsIn a multivariate analysis adjusted for other baseline features, the HT score identified patients at high risk for severe infections (adjusted HR 6.4, 95% CI 3.1 to 13.1). HThigh patients more frequently developed severe infections (40% vs 8%, p<0.0001)—particularly severe bacterial infections (27% vs 0.9%, p<0.0001). Additionally, multivariate analysis of post-CAR-T factors revealed that infection risk was increased by prolonged neutropenia (≥14 days) and corticosteroid use (≥9 days), and decreased with fluoroquinolone prophylaxis. Antibacterial prophylaxis significantly reduced the likelihood of severe bacterial infections in HThigh (16% vs 46%, p<0.001), but not HTlow patients (0% vs 2%, p=n.s.). Collectively, HThigh patients experienced worse median progression-free (3.4 vs 12.6 months) and overall survival (9.1 months vs not-reached), and were hospitalized longer (median 20 vs 16 days). Severe infections represented the most common cause of non-relapse mortality after CAR-T and were associated with poor survival outcomes. A trend toward increased non-relapse mortality in HThigh patients was observed (8.0% vs 3.7%, p=0.09).ConclusionsThese data demonstrate the utility of the HT score to risk-stratify patients for infectious complications and poor survival outcomes prior to CD19 CAR-T. High-risk patients likely benefit from anti-infective prophylaxis and should be closely monitored for potential infections and relapse.

Chimeric antigen receptor T cell (CAR-T) therapy has led to significant improvements in patient survival. However, a subset of patients experience high-grade toxicities, including cytokine release syndrome (CRS) and immune cell-associated hematological toxicity (ICAHT). We utilized IL-2Ra knockout mice to model toxicities with elevated levels of IL-6, IFN-γ, and TNF-α and increased M1-like macrophages. Onset of CRS was accompanied by a reduction in peripheral blood neutrophils due to disruption of bone marrow neutrophil homeostasis characterized by an increase in apoptotic neutrophils and a decrease in proliferative and mature neutrophils. Both nontumor-bearing and Em-ALL tumor-bearing mice recapitulated the cooccurrence of CRS and neutropenia. IFN-γ-blockade alleviated CRS and neutropenia without affecting CAR-T efficacy. Mechanistically, a Th1-Th17 imbalance was observed to drive cooccurrence of CRS and neutropenia in an IFN-γ-dependent manner leading to decreased IL-17A and G-CSF, neutrophil production, and neutrophil survival. In patients, we observed an increase in the IFN-γ-to-IL-17A ratio in the peripheral blood during high-grade CRS and neutropenia. We have uncovered a biological basis for ICAHT and provide support for the use of IFN-γ blockade to reduce both CRS and neutropenia.

Adoptive T-cell immunotherapy is a rapidly growing field and is shifting the paradigm of clinical cancer treatment. Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor T-cell therapy that was initially developed at the National Cancer Institute and has recently been commercially approved by the US Food and Drug Administration for relapsed or refractory aggressive non-Hodgkin's lymphomas including diffuse large B-cell lymphoma and its variants. The ZUMA-1 Phase I and II clinical trials formed the basis of the US Food and Drug Administration approval of this product, and we discuss the particulars of the clinical trials and the pharmacology of axi-cel. In addition, we review the CD19 chimeric antigen receptor T-specific toxicities of cytokine release syndrome and neurotoxicity, which remain the challenges to the safe delivery of this important therapy for aggressive B-cell lymphomas with poor prognosis.

The Metabolic Tumor Volume (MTV) and Tumor Lesion Glycolysis (TLG) has been shown to be independent prognostic predictors for clinical outcome in Diffuse Large B-cell Lymphoma (DLBCL). However, definitions of these measurements have not been standardized, leading to many sources of variation, operator evaluation continues to be one major source. In this study, we propose a reader reproducibility study to evaluate computation of TMV (& TLG) metrics based on differences in lesion delineation. In the first approach, reader manually corrected regional boundaries after automated detection performed across the lesions in a body scan (Reader M using a manual process, or manual). The other reader used a semi-automated method of lesion identification, without any boundary modification (Reader A using a semi- automated process, or auto). Parameters for active lesion were kept the same, derived from standard uptake values (SUVs) over a 41% threshold. We systematically contrasted MTV & TLG differences between expert readers (Reader M & A). We find that MTVs computed by Readers M and A were both concordant between them (concordant correlation coefficient of 0.96) and independently prognostic with a P-value of 0.0001 and 0.0002 respectively for overall survival after treatment. Additionally, we find TLG for these reader approaches showed concordance (CCC of 0.96) and was prognostic for over -all survival (p ≤ 0.0001 for both). In conclusion, the semi-automated approach (Reader A) provides acceptable quantification & prognosis of tumor burden (MTV) and TLG in comparison to expert reader assisted measurement (Reader M) on PET/CT scans.

Chimeric antigen receptor (CAR) T cell therapy is now approved for the standard of care treatment of several types of relapsed or refractory hematologic malignancies. Future advances may extend cellular therapies to solid tumors or even non‐malignant diseases. As patient need grows, a clinical specialty of “cell therapy” may emerge. Here, we envision the needs of a clinical cell therapist to monitor and intervene upon patients receiving cell therapies. These include: (1) monitoring patient T cell quality and the host immune environment to ensure optimal timing for cell therapy. (2) Tumor antigen profiling to personalize CAR T cell targeting. (3) Real‐time monitoring of CAR T cells and circulating tumor DNA to modulate CAR T cell activity to maximize tumor eradication while mitigating toxicity. (4) Monitoring of CAR rejection and anti‐CAR immunity posttreatment to inform re‐dosing and subsequent cell therapy strategies. Armed with these tools, the future Cell Therapist may optimize and personalize treatment to avoid toxicity and improve efficacy universally across CAR designs.

Increasing evidence suggests that the gut microbiome may modulate the efficacy of cancer immunotherapy. In a B cell lymphoma patient cohort from five centers in Germany and the United States (Germany, n  = 66; United States, n  = 106; total, n  = 172), we demonstrate that wide-spectrum antibiotics treatment (‘high-risk antibiotics’) prior to CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is associated with adverse outcomes, but this effect is likely to be confounded by an increased pretreatment tumor burden and systemic inflammation in patients pretreated with high-risk antibiotics. To resolve this confounding effect and gain insights into antibiotics-masked microbiome signals impacting CAR-T efficacy, we focused on the high-risk antibiotics non-exposed patient population. Indeed, in these patients, significant correlations were noted between pre-CAR-T infusion Bifidobacterium longum and microbiome-encoded peptidoglycan biosynthesis, and CAR-T treatment-associated 6-month survival or lymphoma progression. Furthermore, predictive pre-CAR-T treatment microbiome-based machine learning algorithms trained on the high-risk antibiotics non-exposed German cohort and validated by the respective US cohort robustly segregated long-term responders from non-responders. Bacteroides , Ruminococcus , Eubacterium and Akkermansia were most important in determining CAR-T responsiveness, with Akkermansia also being associated with pre-infusion peripheral T cell levels in these patients. Collectively, we identify conserved microbiome features across clinical and geographical variations, which may enable cross-cohort microbiome-based predictions of outcomes in CAR-T cell immunotherapy. Conserved microbiome features across clinical and geographical variations may enable microbiome-based predictions of outcomes in CD19-targeted CAR-T cell immunotherapy

Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for relapsed/refractory large B cell lymphoma (LBCL) and has treatment with similar efficacy across conventional LBCL subtypes. Toward patient stratification, we assessed whether tumor immune contexture influenced clinical outcomes after axi-cel. We evaluated the tumor microenvironment (TME) of 135 pre-treatment and post-treatment tumor biopsies taken from 51 patients in the ZUMA-1 phase 2 trial. We uncovered dynamic patterns that occurred within 2 weeks after axi-cel. The biological associations among Immunoscore (quantification of tumor-infiltrating T cell density), Immunosign 21 (expression of pre-defined immune gene panel) and cell subsets were validated in three independent LBCL datasets. In the ZUMA-1 trial samples, clinical response and overall survival were associated with pre-treatment immune contexture as characterized by Immunoscore and Immunosign 21. Circulating CAR T cell levels were associated with post-treatment TME T cell exhaustion. TME enriched for chemokines (CCL5 and CCL22), γ-chain receptor cytokines (IL-15, IL-7 and IL-21) and interferon-regulated molecules were associated with T cell infiltration and markers of activity. Finally, high density of regulatory T cells in pre-treatment TME associated with reduced axi-cel–related neurologic toxicity. These findings advance the understanding of LBCL TME characteristics associated with clinical responses to anti-CD19 CAR T cell therapy and could foster biomarker development and treatment optimization for patients with LBCL. Analysis of tumor biopsies from the pivotal phase 1/2 ZUMA-1 trial identifies pre-treatment T cell–related characteristics that are associated with clinical response and neurologic toxicity after anti-CD19 CAR T cell therapy in patients with large B cell lymphoma.

BackgroundAutologous CD19 chimeric antigen receptor (CAR) T-cell therapy leads to durable responses and improved survival in patients with relapsed or refractory large B-cell lymphoma (R/R LBCL). Among approved CAR T-cell products, axicabtagene ciloleucel (axi-cel; CD19/CD28) has greater real-world efficacy and cytokine-associated toxicity than tisagenlecleucel (tisa-cel; CD19/4-1BB), for reasons that are poorly understood.MethodsHere we report single-cell RNA sequencing (scRNA-seq) of 57 pre-infusion CAR T-cell products from axi-cel (n=39) and tisa-cel (n=18) patients treated as standard-of-care for R/R LBCL, and their biological associations with clinical outcomes. In vitro CAR manufacturing conditions mimicking those known for axi-cel and tisa-cel were performed using CD19/CD28z or CD19/4-1BBz constructs.ResultsScRNA-seq revealed that axi-cel and tisa-cel are markedly different products. Axi-cel is comprised of more CD4 central memory, CD8 central memory, and CD8 effectors, whereas tisa-cel is comprised of more proliferative CD4 and CD8 cells. Across multiple T-cell subsets, axi-cel had greater expression of immune response pathways and protein synthesis and trafficking pathways versus tisa-cel. On comparison of infusion product CAR transgene-positive (CAR+) cells to CAR transgene-negative (CAR−) T cells, axi-cel CAR+ cells had vastly different gene expression than axi-cel CAR− cells. Unexpectedly, tisa-cel CAR+ cells were highly similar to tisa-cel CAR− cells. Under recapitulated CAR-T manufacturing conditions known to be used for axi-cel and tisa-cel, we found that CAR+ cells differed from CAR− cells early after manufacturing yet became more similar to CAR− cells after prolonged expansion. Prolonged time in expansion culture, as used during tisa-cel manufacturing, greatly decreased naïve and central memory T-cell subsets.ConclusionsFollowing manufacture, axi-cel is less differentiated and has greater immune activation compared with tisa-cel, potentially accounting for its greater efficacy and toxicity in patients. Our data support the conclusion that tisa-cel is adversely affected by its manufacturing rather than by the CAR construct.

Chimeric antigen receptor T‐cell therapy with axicabtagene ciloleucel (axi‐cel) has considerably improved survival in adults with relapsed/refractory large B‐cell lymphoma. This study reports patient‐reported outcomes (PROs) such as quality of life (QOL) and toxicity in the first 90 days after treatment. Hematologic cancer patients treated with axi‐cel (N = 103, mean age = 61, 39% female) completed SF‐36 or PROMIS‐29 QOL questionnaires prior to treatment and 90 days after. PRO‐Common Terminology Criteria for Adverse Events toxicity items were completed by patients at baseline and 14, 30, 60, and 90 days after treatment. Mixed models examined change in PROs over time. From preinfusion to 90 days later, patients reported improvements in physical functioning, pain, and fatigue (ps < 0.01), but worsening of anxiety (p = 0.02). Patient‐reported toxicities worsened by day 14 with improvement thereafter. The five most severe symptoms at day 14 included fatigue, decreased appetite, dry mouth, diarrhea frequency, and problems with concentration. Results indicate improvement in some domains of QOL over time with transient patient‐reported toxicities. From pre‐chimeric antigen receptor (CAR) T‐cell therapy infusion to 90 days later, there were significant improvements in physical functioning and reductions in pain and fatigue, but a significant worsening of anxiety. Patient‐reported toxicities worsened by day 14 with improvement thereafter.