DNA methyltransferase inhibitor decitabine plus anti-PD-1 (DP) combination therapy was effective in relapsed/refractory classic Hodgkin lymphoma (cHL). However, a subset of patients experienced primary resistance or relapse/progression after DP therapy. In this study, we evaluated the efficacy and safety of a triplet regimen consisting of the histone deacetylase inhibitor chidamide, decitabine and anti-PD-1 camrelizumab (CDP) in 52 patients with relapsed/refractory cHL who had previously received DP therapy (NCT04233294). CDP treatment was well-tolerate and resulted in an objective response rate of 94% (95% CI, 84-99%), with 50% (95% CI, 36-64%) of patients achieving complete response (CR). Notably, all patients who were recalcitrant to previous DP treatment exhibited therapeutic responses following CDP therapy, although their CR rate was lower compared to patients responsive to prior DP. Overall, the median progression-free survival following CDP therapy was 29.4 months. Through single-cell RNA sequencing of pre-treatment and on-treatment cHL tumor biopsies, we observed the heterogeneity of rare malignant Hodgkin Reed/Sternberg (HRS)-like cells. The classical CD30+ HRS-like cells interacted with the abundant immunosuppressive IL21+CD4+ T helper cells, forming a positive feedback loop that supported their survival. In contrast, the CD30- HRS-like cell population showed potential resistance to anti-PD-1 immunotherapy. CDP treatment promoted the activation of diverse tumor-reactive CD8+ T cells and suppressed the proliferation of IL21+CD4+ T cells by inhibiting STAT1/3 signaling, thereby alleviating their immunosuppressive effects. These findings provide insights into the cHL microenvironment that contributes to anti-PD-1 resistance and highlight the therapeutic effectiveness of dual epi-immunotherapy in overcoming immunotherapy resistance.

Background: Allogeneic CAR T-cell therapy faces challenges such as limited persistence and host rejection. Recent research has bolstered its viability by modifying genes like B2M, although new challenges, such as NK cell targeting, have surfaced. Through CRISPR screening, we have identified that knocking out an intramembrane-cleaving aspartyl protease prevents it from cutting glycosyltransferases, thereby influencing glycan composition. This alteration enhances glycosylation levels, equipping immune cells with a glycan shield that impacts immune responses and the initiation of activation-induced cell death (AICD). Thereby, it not only combats host rejection but also improves the potency of allo-CAR T cells. Engineered proteaseKO/TCRKO/anti-CD19 CAR T cells (ET-901) resisted allogeneic killing and maintained anti-tumor effects without causing GvHD, marking a significant advancement in allogeneic CAR T-cell therapy. Methods: ET-901 is being evaluated in a phase 1 trial at a single center for patients with r/r B-NHL. The trial follows a 3+3 dose escalation design, with subsequent expansion at the recommended Phase 2 dose (RP2D). Eligible patients must have an ECOG performance status of 0-2 with no prior history of allo-HSCT or CAR-T cell therapy. The primary objectives of the trial are to determine the safety of ET-901 and establish the RP2D. Following lymphodepletion of fludarabine (30-50 mg/m2/d) and cyclophosphamide (500-1000 mg/m2/d) for a duration of 3 days, patients receive a single-dose infusion of ET-901 at escalating doses of 1*10e6/kg, 3*10e6/kg, and 10*10e6/kg. Pharmacokinetic samples were collected during the follow-up period. Results：Out of the initial 20 screened patients, 9 were enrolled and underwent CAR-T infusion from September 6, 2023, to May 31, 2024. All enrolled 9 patients had advanced disease (Ann Arbor stage III-IV). The median number of prior treatment lines was 4 and two-thirds of patients had refractory disease. The median sum of product diameters (SPD) was 7,660 mm² (range: 1,710 to 43,400 mm²), and 4 patients had bulky disease (≥7∙5 cm). Notably, extranodal site involvement was observed in 5 out of 9 cases, complicating treatment with CAR-T therapy. No dose-limiting toxicities (DLTs) or GvHD were observed within 28 days post-infusion. Common adverse events among patients included lymphopenia, anemia, thrombocytopenia, and cytokine release syndrome (CRS), with grade 3 occurring in 3 patients (33%). CRS typically started 1 day after infusion and lasted a median of 7 days. Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 3 patients (33%), with onset at a median of 5 days post-infusion, lasting 3 days. All events were resolved, and cytokine levels normalized within 10 days. The objective response rate was 100%, with 66.7% complete responses and 33.3% partial responses. Of the participants, 5 had ongoing responses, 3 experienced progressive disease. The median peak CAR vector copy number in peripheral blood was 123,529.4 copies/μg. The peak level of CD3-CAR+T cells was 49.2 cells/μl, with the area under the curve (AUC) from days 0 to 28 being 104.5 cells/μl. CAR-T cell expansion correlated with dose and disease burden, peaking at 7 days post-infusion. Conclusions: This study advances allogeneic CAR T-cell therapy for B-cell malignancies, addressing challenges such as limited persistence and rejection. Employing CRISPR to modify the certain protease enhances the resistance of T cells to immune attacks and AICD, maintaining their anti-tumor efficacy without causing GvHD. The phase 1 trial of ET-901 in relapsed/refractory B-NHL patients showed no dose-limiting toxicities, with observed treatment-related adverse events being manageable. All patients demonstrated objective responses, with significant CAR-T cell expansion, confirming the engineered cells' long-term immune privilege and activity. This represents a significant step in making allogeneic CAR T-cell therapy more viable and effective.

Glycosphingolipids (GSLs) are abundantly expressed in cancer cells. The effects of GSL-targeted immunotherapies are not fully understood. Here, we show that the inhibition of GSL synthesis with the UDP-glucose ceramide glucosyltransferase inhibitor eliglustat can increase the exposure of the major histocompatibility complex (MHC) and tumour antigen peptides, enhancing the antitumour response of CD8+ T cells in a range of tumour models. We therefore conducted a proof-of-concept phase I trial on the combination of eliglustat and an anti-PD-1 antibody for the treatment of advanced cancers (NCT04944888). The primary endpoints were safety and feasibility, and the secondary endpoint was antitumor activity. All prespecified endpoints were met. Among the 31 enrolled patients, only 1 patient experienced a grade 3 adverse event (AE), and no grade 4 AEs were observed. The objective response rate was 22.6% and the disease control rate reached 71%. Of the 8 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer, one achieved complete response and two each had partial response and stable disease. In summary, inhibiting the synthesis of GSLs might represent an effective immunotherapy approach. Glycosphingolipids (GSLs) are abnormally expressed in cancer cells. Here, in addition to showing that inhibition of the synthesis of GSLs with eliglustat promotes anti-tumor immune responses in preclinical models, the authors report the results of a phase I trial of eliglustat and anti-PD-1 antibodies for the treatment of advanced cancers.

Platinum-resistant or refractory ovarian cancer (PROC) remains without immunotherapy approval and dismal prognosis, emphasizing the urgent need for novel therapies. This phase 2, single-blind, placebo-controlled, randomized trial evaluated the safety and efficacy of manganese chloride or placebo plus sintilimab, nab-paclitaxel and cisplatin in these patients. 84 patients were randomized to the Mn2+ (n=55) or placebo (n=29) arm. The primary endpoint of objective response rate (ORR) was met at 61.8% in the Mn2+ and 13.8% in placebo group. The secondary endpoints of median PFS (9.8 vs. 3.9 months), OS (21.4 vs. 7.9 months) and DOR (14.9 vs. 1.8 months) were significantly prolonged in the Mn2+ group. No significant differences in AEs and quality of life were document during the treatment period. The serum cytokines and scRNA-seq evidenced the cGAS-STING agonist function of Mn2+. Our study supported Mn2+-priming immunochemotherapy as a promising treatment regimen for PROC patients. ClinicalTrials.gov identifier: NCT03989336.

Background: Preclinical trial has demonstrated that sequential use of Selinexor and Anti-CD19 directed chimeric antigen receptor modified T-Cell therapy (CART19) cells might improve the anti-tumor efficacy of CART 19 cells against lymphoma cells. However, the efficacy and safety of CART19 combined with Selinexor in lymphoma patients is unknown. We report preliminary data from a phase 2 trial of sequential use of Selinexor and CART19 in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (R/R B-NHL). Methods: We performed a multicenter, prospective, phase II, open-label clinical study of sequential use of Selinexor and CART19 in R/R B-NHL. Patients received Selinexor as a bridging therapy (40–60 mg) with a weekly for three weeks prior to CART19 infusion. Over all response (ORR), duration of response (DOR) and safety were evaluated as primary objectives. This study is registered with ClinicalTrials.gov, NCT05322330. Results: Between February 10, 2022, and February 10, 2023, 6 patients were enrolled. Four patients with diffuse large B-cell lymphoma, one mantle cell lymphoma and one Burkitt lymphoma received Selinexor 40mg and CART19 treatment. The median age was 55.5 years (range 34–77), 3 (50.0%) of 6 patients had refractory disease, 5 (83.3%) of 6 patients had extranodal involvement and the median prior systemic therapy was 2 (range 2–5), 5 (83.3%) of 6 patients had evaluated LDH prior to Selinexor administration. Median on-study follow-up was 9.68 months (range 2.53–12.17). 4 (66.7%) of 6 patients had an overall response. Cytokine release syndrome (CRS) was the most common adverse event, occurring in all 6 (100.0%) patients [66.7% was grade 1–2 and 33.3% was grade 3]. No neurotoxicity was observed. The most common grade 3–4 adverse events were neutropenia (5 [83.3%] of 6 patients), thrombocytopenia (4 [66.7%]), and anemia (3 [50.0%]). No treatment-related grade 5 adverse event occurred. Furthermore, our data showed that the use of Selinexor resulted in a higher proportion of CD8+central memory T cell phenotypes (P = 0.04) while having no effect on CD4+ central memory T cell phenotypes (Figure 1). Encore Abstract - previously submitted to ASCO 2023 Keywords: Cellular therapies, Combination Therapies, Ongoing Trials No conflicts of interests pertinent to the abstract.

Case selection criteria;Methods;Figure Legends

Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). With increasing approval of CAR T-cell products and advances in CAR T cell therapy, CAR T cells are expected to be used in a growing number of cases. However, CAR T-cell-associated toxicities can be severe or even fatal, thus compromising the survival benefit from this therapy. Standardizing and studying the clinical management of these toxicities are imperative. In contrast to other hematological malignancies, such as acute lymphoblastic leukemia and multiple myeloma, anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features, most notably local cytokine-release syndrome (CRS). However, previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL. Consequently, we developed this consensus for the prevention, recognition, and management of these toxicities, on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions. This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management, and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.

Figure 5. PD-1 level in tumor-infiltrated T-cells.

Abstract Patients with relapsed/refractory classical Hodgkin lymphoma (cHL) achieve complete response (CR) after decitabine‐plus‐camrelizumab therapy, while long‐term outcome especially after treatment discontinuation remains unclear. We present a retrospective analysis of 87 relapsed/refractory cHL patients who acquired CR after decitabine‐plus‐camrelizumab. Patients were divided into two groups and received consolidation treatment every 3–4 or 6–12 weeks, and 1‐year of continuous CR was guaranteed for treatment cessation. At a median follow‐up of 5.3 years, the median relapse‐free survival (RFS) after achieving CR with decitabine‐plus‐camrelizumab therapy was 4.5 years, and patients underwent consolidation per 3–4 weeks might have longer RFS. The baseline percentage of peripheral central memory T cells was not associated with RFS, while patients with higher pretreatment serum levels of interleukin‐6 (IL‐6) and lactate dehydrogenase (LDH) had significantly shorter RFS and increased risk for disease recurrence. Fifty‐seven patients completed and discontinued decitabine‐plus‐camrelizumab, and their median RFS had not been reached. The 2‐year RFS rate after treatment cessation was 78% (95% CI, 67–90%). Patients in the high‐risk subgroup with higher pretreatment IL‐6 and LDH levels showed poor treatment‐free remission. Moreover, decitabine‐plus‐camrelizumab therapy was safe and cost‐effective. In conclusion, patients who obtained CR with decitabine‐plus‐camrelizumab and received consolidation per 3–4 weeks can achieve long‐term remission after treatment discontinuation.

Lymphocyte recovery is a probable indictor of response.

Although chimeric antigen receptor (CAR) T cells have become an important treatment option for patients with relapsed/refractory B-cell malignancies, more than 60% of patients with diffuse large B-cell lymphoma (DLBCL) treated with CAR-T cell therapies fail to achieve a durable response. To reveal changes in CAR-T cell therapy and identify response biomarkers, we conducted a retrospective analysis of pre-manufacture source T cells and CAR-T cell products and their association with outcome in 58 patients with r/rDLBCL who received tandem CD19/CD20 CAR-T cell therapy. We performed bulk RNA-Seq, single-cell RNA-Seq, and paired T cell receptor sequencing on CAR-T cell products and pre-manufacture T cells from DLBCL patients. We note that a CD8+ stem cell-like memory T cell population with a higher proportion and enhanced activating capacity of the CAR-T cell products was key to achieving durable clinical response. By analysing autologously-derived, pre-manufacture T cells, our data suggest that heterogeneity in the cellular and molecular features of pre-manufacture T cells contribute to the variation in efficacy after CAR-T cell therapy in DLBCL. The differences in anti-tumour efficacy of CAR-T cells among patients with different clinical outcomes appear to be due to the loss of CCR7 gene expression, coupled with increased expression of activation- and inhibitor-related genes in the CD8+ naïve-T cell populations among the apheresis T cells from patients with a poor molecular response. These findings significantly advance our understanding of the underlying molecular determinants of pre-manufacture T cell function.

Background: Tandem CD19/CD20 CAR T cells, which got two scFvs connected to a single molecule with different antigen specificities simultaneously, not just showed broad antigen coverage, yet additionally had robust antitumour activity in vitro. The best overall response rate was 78% with 70% achieving a CR. Here, we report updated clinical outcomes from this trial. Methods: 87 patients with R/R B-NHL after ≥ 2 lines of therapy (including an anti-CD20 mAb plus an alkylating agent) recruited between 2017.05 and 2020.01, which underwent leukapheresis and conditioning chemotherapy followed by a Tandem CD19/CD20 CAR T cells at doses of 0.5 - 8×106/kg of body weight. The updated follow-up analysis was mainly in median PFS, median OS, and median EFS. Besides, survival status of patients after CAR T failure were also observed in the follow-up data. Results: Up to 2022.5.10, the median follow-up time was 38.3 months, 40 patients (45.98%) still keep ongoing response, and the median PFS was 33.17 months, with 49.52% of 3-year PFS rate; the median EFS was 27.6 months, with 47.51% of 3-year EFS rate. The median OS was not reached, with 68.6% of 3-year OS rate. Nonrelapse mortality was 4.4%. Among 39 patients (44.83%) experienced PD after tandem CD19/CD20 CAR T infusion, best response was 54% CR and 10% partial response (PR); 36% were primary refractory, the median PFS was 6.03 months, and the median OS was 25.2 months. Survival data were statistically analysed for patients after CAR T failure, the median follow-up was 26.77 months , and the median OS was 16.37 months. Conclusions: With 3-year follow-up, Tandem CD19/CD20 CAR T cells demonstrated substantial and continued benefits in patients with r/r B-NHL. High CR rates lead to sustained remission and durability, with a long-term median PFS and high percentage of patients in ongoing response at data cutoff, maintained a manageable safety profile, with no new safety signals. For the patients failure after tandem CD19/CD20 CAR T treatment, other anti-tumor regimens, such as bispecific antibodies, target drugs, immunomodulator, secondary CAR T, radiotherapy and so on, could also appeared to attain efficacy outcomes to improve these patient's survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Increasing the remission rate and reducing the recurrence rate can improve the clinical efficacy of chimeric antigen receptor (CAR) T cell therapy in recurrent/refractory non-Hodgkin lymphoma (r/rNHL). In this open-label, single-arm phase I/II trial, 87 patients with r/rNHL, including 58 patients with aggressive diffuse large B-cell lymphoma and 24 with high tumour burden, received an infusion at doses of 0.5 × 10 6 –8 × 10 6 TanCAR7 T cells per kilogram of body weight after conditioning chemotherapy. The best overall response rate was 78% (95% confidence interval [CI], 68–86); response rates were consistent across prognostic subgroups. The median follow-up was 27.7 months. The median progression-free survival was 27.6 months (95% CI, 11 to not reached). Cytokine release syndrome (CRS) occurred in 61 patients (70%) with 60% of cases being grade 1 or 2 and 10% being grade 3 or greater. Grade 3 CAR T cell-related encephalopathy syndrome (CRES) occurred in 2 patients (2%). Two patients died from treatment-associated severe pulmonary infection, and one died from CRS-related pulmonary injury between 1 and 3 months post infusion. Long-term remissions were observed following the use of TanCAR7 T cells in r/rNHL with a safety profile that included CRS but few cases of CRES.

Background Programmed death-1 (PD-1) blockade monotherapy induced durable remission in a subset of patients with relapsed/refractory classical Hodgkin lymphoma (cHL). We asked whether the anti-PD-1 agent, camrelizumab, combined with the DNA demethylating agent, decitabine, improves progression-free survival (PFS) in patients with relapsed/refractory cHL over camrelizumab alone.Methods This extended follow-up of an ongoing randomized phase II trial analyzed PFS among patients enrolled from January 2017 through July 2018. Sixty-one patients with relapsed/refractory cHL who were clinically naïve to PD-1 blockade and had received ≥2 previous therapies were randomized 1:2 to receive either camrelizumab (200 mg) monotherapy or camrelizumab (200 mg, day 8) combined with decitabine (10 mg/day, days 1–5) every 3 weeks.Results With a median follow-up of 34.5 months, complete remission was 79% (95% CI 63% to 90%) in the decitabine-plus-camrelizumab group versus 32% (95% CI 13% to 57%) in the camrelizumab group (p=0.001). Median duration of response was not reached in the decitabine-plus-camrelizumab group, with an estimated 63% (95% CI 46% to 75%) of patients maintaining a response at 24 months. Median PFS with decitabine-plus-camrelizumab therapy was 35.0 months (95% CI not reached) and 15.5 months (95% CI 8.4 to 22.7 months) with camrelizumab monotherapy (HR, 0.46; 95% CI 0.21 to 1.01; p=0.02). Female gender, lower tumor burden, and fewer previous therapies were favorable prognostic factors for durable remission with camrelizumab monotherapy. The PFS benefits of decitabine-plus-camrelizumab versus camrelizumab were observed in most subgroups, especially in patients with relative larger tumor burdens and those treated with ≥3 prior therapies. After decitabine-plus-camrelizumab treatment, the percentage increase of circulating peripheral central memory T-cells correlated with both improved clinical response and PFS, suggesting a putative biomarker of decitabine-plus-camrelizumab therapy for cHL.Conclusions Decitabine-plus-camrelizumab results in longer PFS compared with camrelizumab alone in patients with relapsed/refractory cHL.Trial registration numbers NCT02961101 and NCT03250962.

e19515 Background: The anti-PD-1 combination therapy significantly improves clinical outcomes in patients with relapsed/refractory classical Hodgkin lymphoma (cHL), and up to 71% of patients who receive decitabine-plus-anti-PD-1 camrelizumab could achieve a complete response. However, a subset of patients is recalcitrant to decitabine-plus-camrelizumab and half of patients might experience disease progression within three years. Effective treatment regimens for those with relapsed or progressive cHL who failed decitabine-plus-camrelizumab are needed. This Phase II study was designed to assess the safety and efficacy of the combination of decitabine-plus-camrelizumab and chidamide, a histone deacetylase inhibitor, in decitabine-plus-camrelizumab resistant cHL patients. Methods: Patients with relapsed/refractory cHL who had primary resistance or progressed/relapsed on decitabine-plus-camrelizumab were enrolled and administrated with chidamide at 10 mg (days 1 to 4) and 20 mg (days 8, 11,15 and 18); plus decitabine at 10 mg (days 1 to 5); and camrelizumab at 200 mg (day 6), every 3 weeks. Safety was assessed by CTCAEv5.0, and antitumor response by PET-CT according to the revised Lugano classification. The primary endpoint was objective response rate. Recruitment is ongoing. This trial is registered with ClinicalTrial.gov number, NCT04233294. Results: Between January 19, 2020, and January 31, 2021, nineteen patients with relapsed/refractory cHL after relapse or progression on decitabine-plus-camrelizumab were enrolled. A median of 20 cycles of prior decitabine-plus-camrelizumab was given (range, 4-28). Fourteen patients completed response evaluation with a median follow-up of 5.7 months. All eligible patients received this triplet-agent regimen with a median of 8 cycles (range, 3 to 12). Thirteen of the fourteen evaluated patients (93%) had an objective response, including six acquiring a complete remission (43%) and seven reaching a partial response (50%). The most common adverse events were leukocytopenia (58%; grade 3: 16%), nausea (53%) and hypertriglyceridemia (26%). No immune-related adverse events were observed. Conclusions: The preliminary result shows a high objective response rate with the combination of chidamide, decitabine and camrelizumab in patients with resistance to decitabine-plus-camrelizumab therapy. The addition of chidamide to decitabine-plus-camrelizumab has an acceptable safety profile, and does not trigger immune-related adverse events. Clinical trial information: NCT04233294.

Programmed cell death protein-1 (PD-1)-mediated immunosuppression has been proposed to contribute to the limited clinical efficacy of chimeric antigen receptor T (CAR-T) cells in solid tumors. We generated PD-1 and T cell receptor (TCR) deficient mesothelin-specific CAR-T (MPTK-CAR-T) cells using CRISPR-Cas9 technology and evaluated them in a dose-escalation study. A total of 15 patients received one or more infusions of MPTK-CAR-T cells without prior lymphodepletion. No dose-limiting toxicity or unexpected adverse events were observed in any of the 15 patients. The best overall response was stable disease (2/15 patients). Circulating MPTK-CAR-T cells peaked at days 7-14 and became undetectable beyond 1 month. TCR-positive CAR-T cells rather than TCR-negative CAR-T cells were predominantly detected in effusion or peripheral blood from three patients after infusion. We further confirmed the reduced persistence of TCR-deficient CAR-T cells in animal models. Our results establish the preliminary feasibility and safety of CRISPR-engineered CAR-T cells with PD-1 disruption and suggest that the natural TCR plays an important role in the persistence of CAR-T cells when treating solid tumors.

Abstract Purpose: Programmed death-1 (PD-1) blockade monotherapy is effective in relapsed/refractory classical Hodgkin lymphoma (cHL), but a subset of patients is recalcitrant to PD-1 inhibitors and only a minority of patients achieves durable remission. Effective treatment regimens for those with relapsed/progressive cHL after single-agent anti-PD-1 are urgently needed. Anti-PD-1 combination with the DNA-demethylating agent decitabine showed positive preliminary results in our test cohort patients who were resistant to anti-PD-1. Here, we assess the efficacy of decitabine plus anti-PD-1 therapy in an expansion cohort and after longer follow-up. Patients and Methods: We present the response and progression-free survival rates from patients with relapsed/refractory cHL who relapsed/progressed after prior anti-PD-1 monotherapy, and who received decitabine (10 mg/day, days 1–5) plus the anti-PD-1 camrelizumab (200 mg, day 8), every 3 weeks in a phase II trial (ClinicalTrials.gov: NCT02961101 and NCT03250962). Results: Overall, 51 patients (test cohort: 25, expansion cohort: 26) were treated and 50 evaluated for efficacy. The objective response rate was 52% [nine complete responses (CR); 36%] in the test cohort, and 68% (six CRs; 24%) in the expansion cohort. Median progression-free survival with decitabine plus camrelizumab was 20.0 and 21.6 months, respectively, which was significantly longer than that achieved with prior anti-PD-1 monotherapy. Durable response was observed in an estimated 78% of patients who achieved CR at 24 months. After decitabine plus camrelizumab, the ratio increase of circulating peripheral central memory T cells directly correlated with both clinical response and progression-free survival. Conclusions: Decitabine plus camrelizumab is associated with high response rates and long-term benefits in patients with relapsed/refractory cHL who failed PD-1 inhibitors.

BackgroundThe prognosis of patients with unresectable or metastatic biliary tract cancer (BTC) is unacceptably low. This study aimed to determine the efficacy, safety and predictive biomarkers of the immune checkpoint inhibitor nivolumab in combination with chemotherapy in advanced BTCs.MethodsIn this open-label, single-arm, phase II trial, a chemotherapy and immunotherapy combination consisting of gemcitabine 1000 mg/m2, cisplatin 75 mg/m2and nivolumab 3 mg/kg was administered every 3 weeks for up to six cycles. Maintenance treatment with gemcitabine plus nivolumab was administered to patients achieving disease control following the combination therapy. The primary outcome was the objective response rate. Secondary outcomes included safety, disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). The exploratory objective was to assess biomarkers for predicting clinical response and prognosis.ResultsThirty-two patients with a median age of 60 (range 27–69) years were enrolled. As of September 31, 2019, the median follow-up was 12.8 (95% CI 10.8 to 14.8) months. Twenty-seven response-evaluable patients received a median of 4 (IQR, 3–6) cycles of combination therapy, of whom 15 (55.6%) patients achieved an objective response, including 5 (18.6%) with a complete response (CR), and the DCR was 92.6%. Of the six patients in cohort A who were resistant to gemcitabine-based or cisplatin-based chemotherapy, one achieved CR and one achieved partial response. Thirteen of 21 chemotherapy-naive patients (61.9%) in cohort B achieved an objective response. The median PFS of all patients in cohorts A+B was 6.1 months. The median OS was 8.5 months, with a 33.3% 12-month OS rate. The most frequent grade 3 or higher adverse events were thrombocytopenia (56%) and neutropenia (22%). Fitness might be a biomarker for predicting clinical response. On-therapy changes in serum soluble FasL, MCP-1 and interferon-γ were correlated with prognosis.ConclusionsNivolumab in combination with gemcitabine and cisplatin offers promising efficacy and a manageable safety profile for patients with advanced BTCs.Trial registration numberNCT03311789

Recent immunotherapy using chimeric antigen receptor-modified(CAR)T cells and immune checkpoint blockade therapies has shown remarkable outcomes in the field of cancer treatment.1,2 In particular,great success has been achieved in B cell acute lymphocytic leukemia(B-ALL)treated with anti-CD19 CART cells.2 However,the loss,mutation,and reduced expression of CD19 are crucial causes for the failure of CAR T cell treatment in leukemia patients.3,4 CD38,a 45-kDa type Ⅱ glycoprotein,is detectable in B-ALL,and several studies have indicated the efficacy and safety of CD38 monoclonal antibodies in clinical applications,suggesting that CD38 represents a suitable therapeutic target for the treatment of B-ALL.5,6 In addition,we developed a CAR against CD38,and our preclinical study indicated that anti-CD38 CAR T(CAR T-38)cells could specifically lyse CD38-positive tumor cells.7 Herein,we present the anti-leukemia ability of CAR T-38 cells in an adult relapsed B-ALL patient after failure of bi-specific CD 19/CD22 CAR T cell treatment,and this administration of CAR T-38 cells was accompanied by the occurrence of target-mediated toxicities and severe and uncontrollable cytokine release syn-drome(CRS).

The current clinical outcome for patients with metastatic pancreatic carcinoma (PC) remains poor. Epidermal growth factor receptor (EGFR) is detectable in PC, suggesting that EGFR is a rational target in PC. We conducted a phase I clinical trial to evaluate the safety and efficacy of autologous anti-EGFR chimeric antigen receptor-modified T (CAR T-EGFR) cells in patients with metastatic PC. The expression levels of EGFR on tumor cells detected by immunohistochemistry were required to be more than 50%. Sixteen patients were enrolled and received one to three cycles of the CAR T-EGFR cell infusion within 6 months (median dose of CART cells: 3.48 x 10(6)/kg; range, 1.31 to 8.9 x 10(6)/kg) after the conditioning regimen with 100 to 200 mg/m(2) nab-paclitaxel and 15 to 35 mg/kg cyclophosphamide. Grade >= 3 adverse events included fever/fatigue, nausea/vomiting, mucosal/cutaneous toxicities, pleural effusion and pulmonary interstitial exudation and were reversible. Of 14 evaluable patients, four achieved partial response for 2-4 months, and eight had stable disease for 2-4 months. The median progression-free survival was 3 months (range, 4-months) from the first cycle of CAR T-EGFR cell treatment, and the median overall survival of all 14 evaluable patients was 4.9 months (range, 2.9-30 months). Decreased EGFR expression on tumor cells was observed in patients who achieved stable disease with shrinkage of metastatic lesions in the liver, and enrichment of central memory T cells in infused cells improved the clinical response. In conclusion, the treatment with CAR T-EGFR cells is safe and effective in patients with metastatic PC. (C) 2020 International Society for Cell & Gene Therapy. Published by Elsevier Inc.