The ratio of intratumoral CD15+ neutrophils to CD8+ lymphocytes predicts recurrence in patients with gastric cancer after curative resection.

BACKGROUND: An elevated neutrophil-to-lymphocyte ratio (NLR) in peripheral blood is an independent prognostic indicator of various cancers. AIMS: In this study, we aimed to investigate the prognostic relevance of the intratumoral immune cell balance in gastric cancer. METHODS AND RESULTS: The study included 82 patients who underwent curative resection for gastric cancer. The intratumoral cluster of differentiation (CD) 15- and CD8-positive cells were evaluated using immunohistochemical staining. Additionally, clinicopathological factors and prognoses were analyzed. Patients with high intratumoral CD15/CD8 ratios had significantly lower overall survival (OS) and relapse-free survival (RFS) compared to those with low CD15/CD8 ratios (p = .0026 and p < .0001, respectively). Additionally, a high CD15/CD8 ratio was associated with lymph node metastasis (p = .019). Patients with high NLR had a significantly lower RFS than those with low NLR (p = .0050). Multivariate analysis revealed that the intratumoral CD15/CD8 ratio, NLR, and venous invasion were independent prognostic indicators of RFS (CD15/CD8 ratio: p < .001, hazard ratio (HR) = 14.7, 95% confidence interval (CI) = 3.8-56.8; NLR: p = .010, HR = 5.4, 95% CI = 1.5-19.6; venous invasion: p = .005, HR = 7.4, 95% CI = 1.8-29.7). CONCLUSION: In summary, we found that the intratumoral CD15/CD8 ratio is an independent prognostic factor following gastric cancer resection and its increase is associated with lymph node metastasis and microscopic lymph vessel invasion. Immunological evaluation with additional aspects of innate immunity may be useful in predicting cancer prognosis.

Grainyhead-like-2, an epithelial master programmer, promotes interferon induction and suppresses breast cancer recurrence.

Type-I and -III interferons play a central role in immune rejection of pathogens and tumors, thus promoting immunogenicity and suppressing tumor recurrence. Double strand RNA is an important ligand that stimulates tumor immunity via interferon responses. Differentiation of embryonic stem cells to pluripotent epithelial cells activates the interferon response during development, raising the question of whether epithelial vs. mesenchymal gene signatures in cancer potentially regulate the interferon pathway as well. Here, using genomics and signaling approaches, we show that Grainyhead-like-2 (GRHL2), a master programmer of epithelial cell identity, promotes type-I and -III interferon responses to double-strand RNA. GRHL2 enhanced the activation of IRF3 and relA/NF-kB and the expression of IRF1; a functional GRHL2 binding site in the IFNL1 promoter was also identified. Moreover, time to recurrence in breast cancer correlated positively with GRHL2 protein expression, indicating that GRHL2 is a tumor recurrence suppressor, consistent with its enhancement of interferon responses. These observations demonstrate that epithelial cell identity supports interferon responses in the context of cancer.

Iberdomide increases innate and adaptive immune cell subsets in the bone marrow of patients with relapsed/refractory multiple myeloma.

Iberdomide is a potent cereblon E3 ligase modulator (CELMoD agent) with promising efficacy and safety as a monotherapy or in combination with other therapies in patients with relapsed/refractory multiple myeloma (RRMM). Using a custom mass cytometry panel designed for large-scale immunophenotyping of the bone marrow tumor microenvironment (TME), we demonstrate significant increases of effector T and natural killer (NK) cells in a cohort of 93 patients with multiple myeloma (MM) treated with iberdomide, correlating findings to disease characteristics, prior therapy, and a peripheral blood immune phenotype. Notably, changes are dose dependent, associated with objective response, and independent of prior refractoriness to MM therapies. This suggests that iberdomide broadly induces innate and adaptive immune activation in the TME, contributing to its antitumor efficacy. Our approach establishes a strategy to study treatment-induced changes in the TME of patients with MM and, more broadly, patients with cancer and establishes rational combination strategies for iberdomide with immune-enhancing therapies to treat MM.

Pharmacodynamic changes in tumor and immune cells drive iberdomide's clinical mechanisms of activity in relapsed and refractory multiple myeloma.

Iberdomide is a next-generation cereblon (CRBN)-modulating agent in the clinical development in multiple myeloma (MM). The analysis of biomarker samples from relapsed/refractory patients enrolled in CC-220-MM-001 (ClinicalTrials.gov: NCT02773030), a phase 1/2 study, shows that iberdomide treatment induces significant target substrate degradation in tumors, including in immunomodulatory agent (IMiD)-refractory patients or those with low CRBN levels. Additionally, some patients with CRBN genetic dysregulation who responded to iberdomide have a similar median progression-free survival (PFS) (10.9 months) and duration of response (DOR) (9.5 months) to those without CRBN dysregulation (11.2 month PFS, 9.4 month DOR). Iberdomide treatment promotes a cyclical pattern of immune stimulation without causing exhaustion, inducing a functional shift in T cells toward an activated/effector memory phenotype, including in triple-class refractory patients and those receiving IMiDs as a last line of therapy. This analysis demonstrates that iberdomide's clinical mechanisms of action are driven by both its cell-autonomous effects overcoming CRBN dysregulation in MM cells, and potent immune stimulation that augments anti-tumor immunity.

Principles of risk assessment in colon cancer: immunity is key.

In clinical practice, the administration of adjuvant chemotherapy (ACT) following tumor surgical resection raises a critical dilemma for stage II colon cancer (CC) patients. The prognostic features used to identify high-risk CC patients rely on the pathological assessment of tumor cells. Currently, these factors are considered for stratifying patients who may benefit from ACT at early CC stages. However, the extent to which these factors predict clinical outcomes (i.e. recurrence, survival) remains highly controversial, also uncertainty persists regarding patients' response to treatment, necessitating further investigation. Therefore, an imperious need is to explore novel biomarkers that can reliably stratify patients at risk, to optimize adjuvant treatment decisions. Recently, we evaluated the prognostic and predictive value of Immunoscore (IS), an immune digital-pathology assay, in stage II CC patients. IS emerged as the sole significant parameter for predicting disease-free survival (DFS) in high-risk patients. Moreover, IS effectively stratified patients who would benefit most from ACT based on their risk of recurrence, thus predicting their outcomes. Notably, our findings revealed that digital IS outperformed the visual quantitative assessment of the immune response conducted by expert pathologists. The latest edition of the WHO classification for digestive tumor has introduced the evaluation of the immune response, as assessed by IS, as desirable and essential diagnostic criterion. This supports the revision of current cancer guidelines and strongly recommends the implementation of IS into clinical practice as a patient stratification tool, to guide CC treatment decisions. This approach may provide appropriate personalized therapeutic decisions that could critically impact early-stage CC patient care.

Translational insights into the genetics and immunobiology of relapsed/refractory follicular lymphoma.

Although follicular lymphoma (FL) is traditionally classified as an indolent subtype of B cell non-Hodgkin lymphoma, clinical trajectories are often diverse based on unique disease biology, and many patients will eventually experience relapse of their disease. Furthermore, progression of disease within 24 months is associated with increased mortality rates for FL. In the last five years, we have witnessed an upsurge in the commercial availability of targeted therapies for relapsed/refractory (R/R) FL, including chimeric antigen receptor-T (CAR-T) products, bispecific T cell engagers (BiTEs), epigenetic modifier therapies, and next-generation Bruton tyrosine kinase (BTK) inhibitors. Furthermore, clinical trial options have increased tremendously and now include combinatorial strategies that exert synergy against malignant germinal center B cells. Here, we provide a 2024 update of novel therapeutic agents whose development has been informed by recent advances in the genetics and immunobiology of R/R FL. Specifically, we emphasize high-value targeted therapeutics, including anti-CD3 x anti-CD20 BiTEs and adoptive T cell therapies. We discuss prospects on selection and sequencing of BiTEs and CAR-T therapies for patients with R/R FL. We underscore the principles of FL pathobiology that are paving way for future drug discovery and shed insight into therapeutic targeting within nodal basins based on our increasing understanding of the FL microenvironment. Finally, we summarize how a greater knowledge of FL immunobiology can inform risk stratification and therapy selection on a personalized basis for R/R FL in 2025.

Rapid response in relapsed follicular lymphoma to novel anti-CD19 CAR-T therapy with pseudo-progression and cytomegalovirus infection: A case report.

CD19-directed chimeric antigen receptor (CAR) T cell therapy has been shown to achieve a considerably durable response in patients with refractory or relapsed B cell non-Hodgkin lymphomas. Most of these CARs were generated by lentivirus. With the exception of Yescarta and Tecartus, few patients with relapsed-/refractory- lymphoma have been treated clinically with a CARs using retroviral vector (RV). Here, we reported a relapsed/refractory grade 2 follicular lymphoma patient with multiple chemotherapy failures, and was treated with a novel CD19 CAR-T cell manufactured from a RV. After tumor burden was reduced with Obinutuzumab and Duvelisib, the patient was infused novel CD19 CAR-T cells at a dose of 3 × 106 cells/ kg. Then he experienced a rapid response and achieved almost complete remission by day 26. Only grade 2 CRS, bilateral submaxillary lymph node enlargement and cytomegalovirus (CMV) infection occurred without neurotoxicity, and the patient's condition improved after a series of symptomatic treatments. In addition, CAR copy number peaked at 532,350 copies/µg on day 15 and continued to expand for 5 months. This may be the first case report of RV preparation of novel CD19 CAR-T cells for direct treatment of recurrent follicular lymphoma. We will observe its long-term efficacy and conduct trials in more patients in the future.

Immunotherapy for esophageal cancer: Where are we now and where can we go.

Immune checkpoint inhibitor therapy has dramatically improved patient prognosis, and thereby transformed the treatment in various cancer types including esophageal squamous cell carcinoma (ESCC) in the past decade. Monoclonal antibodies that selectively inhibit programmed cell death-1 (PD-1) activity has now become standard of care in the treatment of ESCC in metastatic settings, and has a high expectation to provide clinical benefit during perioperative period. Further, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monoclonal antibody has also been approved in the treatment of recurrent/metastatic ESCC in combination with anti-PD-1 antibody. Well understanding of the existing evidence of immune-based treatments for ESCC, as well as recent clinical trials on various combinations with chemotherapy for different clinical settings including neoadjuvant, adjuvant, and metastatic diseases, may provide future prospects of ESCC treatment for better patient outcomes.

Long-term relapse-free survival enabled by integrating targeted antibacteria in antitumor treatment.

The role of tumor-resident intracellular microbiota (TRIM) in carcinogenesis has sparked enormous interest. Nevertheless, the impact of TRIM-targeted antibacteria on tumor inhibition and immune regulation in the tumor microenvironment (TME) remains unexplored. Herein, we report long-term relapse-free survival by coordinating antibacteria with antitumor treatment, addressing the aggravated immunosuppression and tumor overgrowth induced by TRIM using breast and prostate cancer models. Combining Ag+ release with a Fenton-like reaction and photothermal conversion, simultaneous bacteria killing and multimodal antitumor therapy are enabled by a single agent. Free of immune-stimulating drugs, the agent restores antitumor immune surveillance and activates immunological responses. Secondary inoculation and distal tumor analysis confirm lasting immunological memory and systemic immune responses. A relapse-free survival of >700 days is achieved. This work unravels the crucial role of TRIM-targeted antibacteria in tumor inhibition and unlocks an unconventional route for immune regulation in TME and a complete cure for cancer.

Stimulation of tumoricidal immunity via bacteriotherapy inhibits glioblastoma relapse.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by invasive behavior and a compromised immune response, presenting treatment challenges. Surgical debulking of GBM fails to address its highly infiltrative nature, leaving neoplastic satellites in an environment characterized by impaired immune surveillance, ultimately paving the way for tumor recurrence. Tracking and eradicating residual GBM cells by boosting antitumor immunity is critical for preventing postoperative relapse, but effective immunotherapeutic strategies remain elusive. Here, we report a cavity-injectable bacterium-hydrogel superstructure that targets GBM satellites around the cavity, triggers GBM pyroptosis, and initiates innate and adaptive immune responses, which prevent postoperative GBM relapse in male mice. The immunostimulatory Salmonella delivery vehicles (SDVs) engineered from attenuated Salmonella typhimurium (VNP20009) seek and attack GBM cells. Salmonella lysis-inducing nanocapsules (SLINs), designed to trigger autolysis, are tethered to the SDVs, eliciting antitumor immune response through the intracellular release of bacterial components. Furthermore, SDVs and SLINs administration via intracavitary injection of the ATP-responsive hydrogel can recruit phagocytes and promote antigen presentation, initiating an adaptive immune response. Therefore, our work offers a local bacteriotherapy for stimulating anti-GBM immunity, with potential applicability for patients facing malignancies at a high risk of recurrence.

Spatial Distribution of Macrophage and Lymphocyte Subtypes within Tumor Microenvironment to Predict Recurrence of Non-Muscle-Invasive Papillary Urothelial Carcinoma after BCG Immunotherapy.

Non-muscle-invasive papillary urothelial carcinoma (NMIPUC) of the urinary bladder is the most common type of bladder cancer. Intravesical Bacille Calmette-Guerin (BCG) immunotherapy is applied in patients with a high risk of recurrence and progression of NMIPUC to muscle-invasive disease. However, the tumor relapses in about 30% of patients despite the treatment, raising the need for better risk stratification. We explored the potential of spatial distributions of immune cell subtypes (CD20, CD11c, CD163, ICOS, and CD8) within the tumor microenvironment to predict NMIPUC recurrence following BCG immunotherapy. Based on analyses of digital whole-slide images, we assessed the densities of the immune cells in the epithelial-stromal interface zone compartments and their distribution, represented by an epithelial-stromal interface density ratio (IDR). While the densities of any cell type did not predict recurrence, a higher IDR of CD11c (HR: 0.0012, p-value = 0.0002), CD8 (HR: 0.0379, p-value = 0.005), and ICOS (HR: 0.0768, p-value = 0.0388) was associated with longer recurrence-free survival (RFS) based on the univariate Cox regression. The history of positive repeated TUR (re-TUR) (HR: 4.93, p-value = 0.0001) and T1 tumor stage (HR: 2.04, p-value = 0.0159) were associated with shorter RFS, while G3 tumor grade according to the 1973 WHO classification showed borderline significance (HR: 1.83, p-value = 0.0522). In a multivariate analysis, the two models with a concordance index exceeding 0.7 included the CD11c IDR in combination with either a history of positive re-TUR or tumor stage. We conclude that the CD11c IDR is the most informative predictor of NMIPUC recurrence after BCG immunotherapy. Our findings highlight the importance of assessment of the spatial distribution of immune cells in the tumor microenvironment.

Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer.

Importance: The association of tumor-infiltrating lymphocyte (TIL) abundance in breast cancer tissue with cancer recurrence and death in patients with early-stage triple-negative breast cancer (TNBC) who are not treated with adjuvant or neoadjuvant chemotherapy is unclear. Objective: To study the association of TIL abundance in breast cancer tissue with survival among patients with early-stage TNBC who were treated with locoregional therapy but no chemotherapy. Design, Setting, and Participants: Retrospective pooled analysis of individual patient-level data from 13 participating centers in North America (Rochester, Minnesota; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea), including 1966 participants diagnosed with TNBC between 1979 and 2017 (with follow-up until September 27, 2021) who received treatment with surgery with or without radiotherapy but no adjuvant or neoadjuvant chemotherapy. Exposure: TIL abundance in breast tissue from resected primary tumors. Main Outcomes and Measures: The primary outcome was invasive disease-free survival [iDFS]. Secondary outcomes were recurrence-free survival [RFS], survival free of distant recurrence [distant RFS, DRFS], and overall survival. Associations were assessed using a multivariable Cox model stratified by participating center. Results: This study included 1966 patients with TNBC (median age, 56 years [IQR, 39-71]; 55% had stage I TNBC). The median TIL level was 15% (IQR, 5%-40%). Four-hundred seventeen (21%) had a TIL level of 50% or more (median age, 41 years [IQR, 36-63]), and 1300 (66%) had a TIL level of less than 30% (median age, 59 years [IQR, 41-72]). Five-year DRFS for stage I TNBC was 94% (95% CI, 91%-96%) for patients with a TIL level of 50% or more, compared with 78% (95% CI, 75%-80%) for those with a TIL level of less than 30%; 5-year overall survival was 95% (95% CI, 92%-97%) for patients with a TIL level of 50% or more, compared with 82% (95% CI, 79%-84%) for those with a TIL level of less than 30%. At a median follow-up of 18 years, and after adjusting for age, tumor size, nodal status, histological grade, and receipt of radiotherapy, each 10% higher TIL increment was associated independently with improved iDFS (hazard ratio [HR], 0.92 [0.89-0.94]), RFS (HR, 0.90 [0.87-0.92]), DRFS (HR, 0.87 [0.84-0.90]), and overall survival (0.88 [0.85-0.91]) (likelihood ratio test, P < 10e-6). Conclusions and Relevance: In patients with early-stage TNBC who did not undergo adjuvant or neoadjuvant chemotherapy, breast cancer tissue with a higher abundance of TIL levels was associated with significantly better survival. These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early-stage TNBC.

The Prognostic Immune and Nutritional Indices Are Independent Prognostic Factors for Esophageal Cancer Patients Who Receive Curative Treatment.

BACKGROUND/AIM: Recently, the prognostic immune and nutritional index (PINI) was developed and reported to be a promising nutritional and inflammatory prognostic marker. The aim of the present study was to clarify the clinical impact of the PINI for esophageal cancer patients who received curative treatment. PATIENTS AND METHODS: We conducted a retrospective review of medical records and collected data on consecutive esophageal cancer patients who underwent curative resection at Yokohama City University between 2005 and 2020. The PINI was calculated by dividing the serum ALB concentration (g/dl) by the serum monocyte concentration, both of which were measured before surgery. RESULTS: A total of 180 patients were included in this study. The cutoff value of the PINI was 3.0 in the present study. The 3- and 5-year overall survival rates were 45.2% and 33.5%, respectively, in the PINI-low subgroup, and 69.1% and 61.8%, respectively, in the PINI-high subgroup. A multivariate analysis demonstrated that the PINI was an independent prognostic factor for overall survival (hazard ratio=2.091, 95% confidence interval=1.287-3.399, p=0.003). Similar results were observed for recurrence-free survival. When comparing the sites of recurrence between the two groups, the incidence of hematological recurrence was significantly greater in the PINI-low subgroup compared to the PINI-high subgroup (46.8% vs. 21.1%, p<0.001). CONCLUSION: The PINI is a promising nutritional and inflammatory marker for esophageal cancer patients. The PINI might be a useful marker for the treatment and management of esophageal cancer patients.

Identification of a Gene Expression Signature to Predict the Risk of Early Recurrence and the Degree of Immune Cell Infiltration in Triple-negative Breast Cancer.

BACKGROUND/AIM: Patients with triple-negative breast cancer (TNBC) have a high rate of recurrence within 3 years of diagnosis and a high rate of death within 5 years compared to other subtypes. The number of clinical trials investigating various new agents and combination therapies has recently increased; however, current strategies benefit only a minority of patients. This study aimed to identify specific genes that predict patients at high risk of recurrence and the immune status of the tumor microenvironment at an early stage, thereby providing insight into potential therapeutic targets to improve clinical outcomes in TNBC patients. MATERIALS AND METHODS: We evaluated the prognostic significance of microarray mRNA expression of 20,603 genes in 233 TNBC patients from the METABRIC dataset and further validated the results using RNA-seq mRNA expression data in 143 TNBC patients from the GSE96058 dataset. RESULTS: Eighteen differentially expressed genes (AKNA, ARHGAP30, CA9, CD3D, CD3G, CD6, CXCR6, CYSLTR1, DOCK10, ENO1, FLT3LG, IFNG, IL2RB, LPXN, PRKCB, PVRIG, RASSF5, and STAT4) identified in both datasets were found to be reliable biomarkers for predicting TNBC recurrence and progression. Notably, the genes whose low expression was associated with increased risk of recurrence and death were immune-related genes, with significant differences in levels of immune cell infiltration in the tumor microenvironment between high- and low- expression groups. CONCLUSION: Genes reported herein may be effective biomarkers to identify TNBC patients who will and will not benefit from immunotherapy and may be particularly important genes for developing future treatment strategies, including immunotherapy.

Expression of immune-related genes and breast cancer recurrence in women with ductal carcinoma in situ.

BACKGROUND AND AIM: Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer with highly variable clinical behavior, but risk stratification is still challenging. We sought to identify immune-related gene expression signatures of pure DCIS associated with different risks of breast cancer recurrence. METHODS: A retrospective nested case-control study of 143 pure DCIS was performed including 70 women with subsequent ipsilateral breast event (IBE, in situ or invasive; cases) and 73 DCIS women with no IBE and matched for age, tumor size, treatment, hormone receptors/HER2 status, and follow-up time (controls). RNA was extracted from DCIS samples and subjected to next-generation sequencing gene expression analysis of 395 immune-related genes. Correlations between DCIS immune-related gene expression and IBE were analyzed using weighted Cox regression for nested case-control data. RESULTS: Eight immune-related genes were differentially expressed between cases and controls. MAGEA10 expression (present vs. absent) and high expression levels of IFNA17 and CBLB (Q4 vs. Q1) were observed more frequently in DCIS of women with subsequent IBE, mainly invasive (p-valueFDR < 0.05). Conversely, expression of IL3RA1, TAGAP, TNFAIP8, and high expression levels of CCL2 and LRP1 were associated with a lower risk of IBE (p-valueFDR < 0.05). CONCLUSION: This exploratory analysis of pure DCIS showed significant differences in immune-related gene expression profiles between women with and with no subsequent IBE, particularly as invasive IBE. These results, after additional validation, could improve risk stratification and management of DCIS patients.

Thyroglobulin Antibodies and Tumor Epitope-Specific Cellular Immunity in Papillary Thyroid Cancer.

Papillary thyroid carcinoma (PTC) is characterized by T cell infiltration and frequently by the presence of anti-thyroglobulin antibodies (TgAbs). The role of cellular immunity and of TbAbs in this context is a matter of debate. The aim of our study was to correlate the presence of TgAbs, tumor epitope-specific T cells and the clinical outcome of PTC patients. We studied n=183 consecutive patients with a diagnosis of PTC which were treated with total thyroidectomy plus 131I ablation. During a follow-up of in mean 97 months, most of the PTC patients had no signs of tumor relapse (n=157 patients). In contrast, one patient had serum Tg levels above the detection limit and<1 ng/ml, two patients Tg serum levels≥1 ng/ml and<2 ng/ml and n=23 patients had Tg serum levels≥2 ng/ml. Morphological signs of tumor recurrence were seen in 14 patients; all of these patients had serum Tg levels≥2 ng/ml. Importantly, with the exception of one patient, all TgAb positive PTC patients (n=27) had no signs of tumor recurrence as the serum Tg levels were below the assays functional sensitivities. Tetramer analyses revealed a higher number of tumor epitope-specific CD8+T cells in TgAb positive patients compared to TgAb negative PTC patients. In summary, we show that the occurrence of TgAbs may have an impact on the clinical outcome in PTC patients. This might be due to a tumor epitope-specific cellular immunity in PTC patients.

Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results.

Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study's primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×107 cells; n = 3) and dose level 2 (2.5 × 107 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier: NCT05168423 .

The value of bispecific antibodies in relapsed and refractory DLBCL.

Diffuse large B-cell lymphoma (DLBCL) may be cured with anti-CD20 based chemoimmunotherapy in the majority of cases, however, relapsed/refractory disease occurs in 30-40% patients, and despite significant recent therapeutic advances, continues to represent an unmet clinical need. Bispecific antibodies represent a novel class of therapy currently in development for relapsed/refractory B-cell lymphoma. This review discusses the background clinical need, mechanism of action, and clinical data including efficacy and toxicity for bispecific antibodies in DLBCL, focusing on the most advanced class in development; CD20 targeting T-cell engaging antibodies. Emerging possibilities for future use of bispecific antibodies is also discussed, including novel and cytotoxic combination regimens in relapsed and first-line settings.