Cell Therapy In Patients Research Articles

Efficacy of stem cell therapy in patients with chronic liver disease: an umbrella review of systematic reviews.

Stem cell therapy offers promising benefits like modulating immune responses, reducing inflammation, and aiding liver regeneration. This umbrella review seeks to compile evidence from systematic reviews to assess the efficacy of stem cell therapy for improving liver function and survival rates in chronic liver disease patients. We searched electronic databases up to February 15, 2024. The selection process focused on systematic reviews comparing stem cell therapy with standard care or a placebo. The primary outcomes evaluated were changes in liver enzymes, the MELD score, and survival rates. Nested Knowledge software was utilized for screening and data extraction. All statistical analyses were performed using R software, version 4.3. Our umbrella review included 28 systematic reviews. The meta-analysis showcased a notable improvement in survival rates with a pooled RR of 1.487 (95% CI: 1.281 to 1.727). In non-randomized studies, albumin levels exhibited an SMD of 0.786 (95% CI: 0.368 to 1.204), indicating positive therapeutic effects. For ALT, the meta-analysis revealed a decrease in levels with an SMD of -0.499 (95% CI: -0.834 to -0.164), and for AST, an overall SMD of -0.362 (95% CI: -0.659 to -0.066) was observed, suggesting hepatoprotective effects. No significant changes were observed in total bilirubin levels and MELD scores in RCTs. Stem cell therapy exhibits potential as a novel treatment for chronic liver diseases, as it has demonstrated improvements in survival rates and certain liver function markers. More high-quality RCTs are needed in the future to fully ascertain the efficacy of stem cell therapy in this patient population.

Single-cell analysis of anti-BCMA CAR T cell therapy in patients with central nervous system autoimmunity.

Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti-B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8+ CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.

Identification of a Patient Suitable for CAR-T Cell Therapy in the Outpatient Setting: A Vodcast and Case Example.

Chimeric antigen receptor T cell (CAR-T) therapies targeting the CD19 antigen have been associated with high and durable response rates in patients with diffuse large B cell lymphoma (DLBCL). CAR-T cell therapies are commonly administered in the inpatient setting due to the average onset of cytokine release syndrome within the first 3days post infusion, but there has been growing interest in delivering CAR-T cell therapies in the outpatient setting to overcome frequent hospital bed shortages and the high cost of inpatient care. Although this approach could improve access whilst catering to patient preference, it requires a multidisciplinary approach as well as careful patient selection. Herein, Dr. Foley and Dr. Kuruvilla discuss the case of a patient presenting with the ideal profile for CAR-T cell therapy referral whilst also determining the key attributes for eligibility from a clinician's perspective. Solutions for successful outpatient management include proper education, caregiver support, and early referral to ensure a timely infusion. In conclusion, outpatient administration of CAR-T cell therapy in patients with DLBCLs should be assessed on a case-by-case basis.A vodcast feature is available for this article.

A phase I trial of autologous RAK cell immunotherapy in metastatic renal cell carcinoma

BackgroundTreatment of metastatic renal cell carcinoma (mRCC) remains a challenge worldwide. Here, we introduced a phase I trial of autologous RAK cell therapy in patients with mRCC whose cancers progressed after prior systemic therapy. Although RAK cells have been used in clinic for many years, there has been no dose-escalation study to demonstrate its safety and efficacy.MethodsWe conducted a phase I trial with a 3 + 3 dose-escalation design to investigate the dose-related safety and efficacy of RAK cells in patients with mRCC whose cancers have failed to response to systemic therapy (ChiCTR1900021334).ResultsAutologous RAK cells, primarily composed of CD8+ T and NKT cells, were infused intravenously to patients at a dose of 5 × 109, 1 × 1010 or 1.5 × 1010 cells every 28 days per cycle. Our study demonstrated general safety of RAK cells in a total of 12 patients. Four patients (33.3%) showed tumor shrinkage, two of them achieved durable partial responses. Peripheral blood analysis showed a significant increase in absolute counts of CD3+ and CD8+ T cells after infusion, with a greater fold change observed in naive CD8+ T cells (CD8+CD45RA+). Higher peak values of IL-2 and IFN-γ were observed in responders after RAK infusion.ConclusionThis study suggests that autologous RAK cell immunotherapy is safe and has clinical activity in previously treated mRCC patients. The improvement in peripheral blood immune profiling after RAK cell infusion highlights its potential as a cancer treatment. Further investigation is necessary to understand its clinical utility.

Clinical analysis of the correlation between the expression of soluble B cell maturation antigen and the efficacy of chimeric antigen receptor T cell targeting B cell maturation antigen in patients with multiple myeloma

Objective: The effect of bone marrow soluble B cell maturation antigen (sBCMA) expression on the efficacy and side effects of chimeric antigen receptor (CAR) -modified T-cell-targeting B cell maturation antigen (BCMA) in patients with multiple myeloma (MM) . Methods: This study involved 29 patients with relapsed or refractory MM (RRMM) who received humanized anti-BCMA CAR-T cell clinical trials from January 2018 to December 2021. The expression of sBCMA in bone marrow before and after anti-BCMA CAR-T cell treatment was detected by flow cytometry and compared. Results: ①Two months after BCMA CAR-T cell treatment, 20 patients (68.97%) achieved an overall response (OR), whereas nine patients had stable disease (SD) or miner emission (MR). ②The expression of sBCMA in the bone marrow of 20 patients with OR was higher before treatment than after [26 926 (18 215, 32 488) ng/L vs 9 968 (6 634, 11 459) ng/L; P<0.001]; no significant difference was observed in patients with MR and SD [41 187 (33 816, 47 046) ng/L vs. 33 954 (31 569, 36 256) ng/L; P=0.145]; sBCMA expression in patients with OR before CAR-T cell treatment was lower than in patients with MR and SD (P=0.005). ③No significant linear correlation was found between the peak value of CAR-T cells and sBCMA expression in the bone marrow of all 29 patients with RRMM (R(2)=0.035, P=0.330). ④No significant difference in sBCMA expression was found between grades 0-1 CRS group (13 patients) and grades 2-4 CRS group [16 patients; 32 045 (18 742, 40 801) ng/L vs 29 102 (24 679, 38 776) ng/L, P=0.879], nor between grade 0 ICANS group (22 patients) and grade 1-3 ICANS group [seven patients; 30 073 (19 375, 40 065) ng/L vs 33 816 (22 933, 43 459) ng/L, P=0.763]. Conclusion: sBCMA expression in the bone marrow is related to the efficacy of BCMA CAR-T cell therapy in patients with RRMM, but is not significantly correlated with the severity of adverse events. It may serve as a predictive biomarker for the efficacy of BCMA CAR-T cell therapy in these patients.

Abstract CT285: Trial in progress: A phase 1/2 study to investigate the safety and efficacy of OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy in patients (pts) with immune checkpoint inhibitor (ICI)-resistant advanced or metastatic melanoma

Abstract Introduction ICI have improved outcomes for pts with melanoma; however, most pts (~60%) do not achieve long-term survival. Unengineered bulk TIL cell therapy has an objective response rate (ORR) of 31-49% in pts with unresectable or metastatic melanoma (Rohaan NEJM 2022, Chesney JITC 2022), but requires co-administration of systemic high-dose IL2, which is associated with safety risks and limits pt eligibility. OBX-115 TIL are engineered to express regulatable membrane-bound IL15 (mbIL15) under dose-dependent regulation using acetazolamide (ACZ), an FDA-approved small-molecule diuretic, avoiding the need for high-dose IL2. A first-in-human single-institution study (NCT05470283) evaluating the safety of OBX-115 in metastatic melanoma is currently enrolling. The current study (NCT06060613) is enrolling at multiple US sites using centralized manufacturing. Methods This phase 1/2, single-arm, open-label, nonrandomized, multicenter study will assess the safety, tolerability, and efficacy of the OBX-115 engineered autologous TIL cell therapy regimen in pts with unresectable or metastatic melanoma resistant to ICI (Table). Primary objectives of Phase 1 are to characterize safety and tolerability and identify a recommended Phase 2 dose of the OBX-115 regimen; Phase 2 will evaluate efficacy (ORR using RECIST v1.1). Cryopreserved OBX-115 is generated from the pt’s own tumor tissue procured by surgical excision or core biopsy, and is infused after standard- or low-dose (based on clinical eligibility) lymphodepletion (cyclophosphamide and fludarabine). ACZ is administered at cohort-defined doses once daily for up to 10 days, with ACZ redosing at Week 6-8 for 10 days if the initial observed tumor response is less than partial response. No systemic high-dose IL2 is administered. Two sites are open and recruiting pts. TABLE 1. NAND Key Eligibility Criteria Key Inclusion Criteria Key Exclusion Criteria Age ≥18 years Uveal melanoma Histologically confirmed diagnosis of unresectable Stage IIIC, IIID, or Stage IV metastatic melanoma Brain metastasis or leptomeningeal disease Documented radiographic disease progression after systemic therapy containing a PD-1- or PD-L1-blocking antibody (if adjuvant setting, progression during or within 12 weeks after the last dose) Active autoimmune disease, including active uveitis or any other medical illness that would pose increased risks for study participation Received a BRAF inhibitor ± MEK inhibitor if BRAF V600 mutation-positive Prior allogeneic organ transplant, allogeneic cell therapy, or genetically engineered cell therapy (not including autologous stem cell or unengineered TIL cell therapy) ≥1 lesion suitable for OBX-115 generation with expected minimum of 1.5-cm diameter; minimally invasive tumor tissue procurement (core biopsy) may be considered on a case-by-case basis after discussion with the Medical Monitor Systemic steroid therapy &amp;gt;10 mg/day of prednisone or equivalent ≥1 RECIST 1.1-measurable lesion remaining after tumor tissue procurement ECOG performance status 0 or 1 Estimated life expectancy &amp;gt;6 months Citation Format: Sajeve S. Thomas, Jason A. Chesney, Omid Hamid, Gino K. In, Alexander N. Shoushtari, Yazan Samhouri, Parameswaran Hari, Giridharan Ramsingh, Prakash Prabhakar, Lauren Mclaughlin, Allison Betof Warner. Trial in progress: A phase 1/2 study to investigate the safety and efficacy of OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy in patients (pts) with immune checkpoint inhibitor (ICI)-resistant advanced or metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT285.

Abstract CT002: CTX130 allogeneic CRISPR-Cas9-engineered chimeric antigen receptor (CAR) T cells in patients with advanced clear cell renal cell carcinoma: Long-term follow-up and translational data from the phase 1 COBALT-RCC study

Abstract Background: The mainstay of therapy for clear cell renal cell carcinoma (ccRCC), the most prevalent subtype of kidney cancer, includes checkpoint inhibitors (CPIs) and tyrosine kinase inhibitors (TKIs). However, once patients progress on these drug classes, outcomes are poor. Here, we report durable response and stability observed in a Phase 1 dose-escalation study of CTX130™, a CD70-targeting allogeneic CAR T cell therapy in patients with ccRCC. Methods: In this phase I study, patients were recruited from sites in the United States, Europe and Australia. Key eligibility included advanced ccRCC with prior receipt of at least one CPI and TKI. After receipt of standard lymphodepletion with fludarabine and cyclophosphamide for 3 days (dosed at 30 mg/m2 and 500 mg/m2, respectively), patients received infusion of CTX130. Results: Among the 16 patients enrolled and treated in dose escalation, the median age was 63 (range, 53-77) and all were stage IV at the time of enrollment. Patients had received a median of 3 prior lines of therapy (range, 1-6). Doses ranging from 3 × 107 to 9 × 108 CAR T cells were administered, and no dose-limiting toxicities were encountered. Cytokine release syndrome (CRS) was observed in 8 patients (50%); all events were grade 1 or 2. Infections were observed in 4 patients (25%), all deemed to be unrelated to CTX130. No hemophagocytic lymphohistiocytosis, graft-versus host disease or treatment-related neurotoxicity was observed. As of Oct 9, 2023, 1 patient (6.3%) achieved a complete response (CR) (now extending over 36+ months) and 12 additional patients (75%) achieved stable disease (SD) (1 patient in excess of 18 months), reflecting a disease control rate (CR/partial response/SD) of 81.3%. Immunohistochemical staining of baseline and archival tissues show an initial median CD70 expression level of 100% (range, 1-100%), with no substantial antigenic loss at sequential biopsies performed at day 42. Using digital droplet PCR assays of the CAR construct, we assessed expansion. CTX130 was detected in 20 minutes after infusion, declined to a nadir 2-3 days later, followed by rapid expansion between days 7 and 15. In general, expansion increased at each dose level. Conclusions: Updated results from the COBALT-RCC study reinforce both the encouraging antitumor activity and exceptional safety profile of CTX130. The durable CR, now in excess of 3 years, reflects the first and longest seen with allogeneic CAR T cell therapy in refractory solid tumors. A study of CTX131™ (building on CTX130 with CRISPR edits to enhance potency and persistence) is ongoing. Citation Format: Sumanta Kumar Pal, Ben Tran, John B. Haanen, Michael Hurwitz, Adrian Sacher, Neeraj Agarwal, Nizar Tannir, Elizabeth Budde, Simon Harrison, Sebastian Klobuch, Sagar S. Patel, Mary-Lee Dequeant, Qiuling Ally He, Alissa Keegan, Henia Dar, Anna Ma, PK Morrow, Samer A. Srour. CTX130 allogeneic CRISPR-Cas9-engineered chimeric antigen receptor (CAR) T cells in patients with advanced clear cell renal cell carcinoma: Long-term follow-up and translational data from the phase 1 COBALT-RCC study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT002.

A high-content screen of FDA approved drugs to enhance CAR T cell function: ingenol-3-angelate improves B7-H3-CAR T cell activity by upregulating B7-H3 on the target cell surface via PKCα activation

BackgroundCAR T cell therapy is a promising approach to improve outcomes and decrease toxicities for patients with cancer. While extraordinary success has been achieved using CAR T cells to treat patients with CD19-positive malignancies, multiple obstacles have so far limited the benefit of CAR T cell therapy for patients with solid tumors. Novel manufacturing and engineering approaches show great promise to enhance CAR T cell function against solid tumors. However, similar to single agent chemotherapy approaches, CAR T cell monotherapy may be unable to achieve high cure rates for patients with difficult to treat solid tumors. Thus, combinatorial drug plus CAR T cell approaches are likely required to achieve widespread clinical success.MethodsWe developed a novel, confocal microscopy based, high-content screen to evaluate 1114 FDA approved drugs for the potential to increase expression of the solid tumor antigen B7-H3 on the surface of osteosarcoma cells. Western blot, RT-qPCR, siRNA knockdown and flow cytometry assays were used to validate screening results and identify mechanisms of drug-induced B7-H3 upregulation. Cytokine and cytotoxicity assays were used to determine if drug pre-treatment enhanced B7-H3-CAR T cell effector function.ResultsFifty-five drugs were identified to increase B7-H3 expression on the surface of LM7 osteosarcoma cells using a novel high-content, high-throughput screen. One drug, ingenol-3-angelate (I3A), increased B7-H3 expression by up to 100%, and was evaluated in downstream experiments. Validation assays confirmed I3A increased B7-H3 expression in a biphasic dose response and cell dependent fashion. Mechanistic studies demonstrated that I3A increased B7-H3 (CD276) mRNA, total protein, and cell surface expression via protein kinase C alpha activation. Functionally, I3A induced B7-H3 expression enhanced B7-H3-CAR T cell function in cytokine production and cytotoxicity assays.ConclusionsThis study demonstrates a novel high-content and high-throughput screen can identify drugs to enhance CAR T cell activity. This and other high-content technologies will pave the way to develop clinical trials implementing rational drug plus CAR T cell combinatorial therapies. Importantly, the technique could also be repurposed for an array of basic and translational research applications where drugs are needed to modulate cell surface protein expression.

Abstract 3997: PARP inhibitors plus anlotinib as bridging therapy for TGFβ-insensitive CAR-T cell therapy targeting MSLN and CD19 in advanced ovarian cancer

Abstract Background: The efficacy of chimeric antigen receptor (CAR) T cell therapy remains modest for the treatment of solid tumors due to restricted T cell infiltration and immunosuppressive tumor microenvironment (TME). Leveraging the window of opportunity between leukapheresis and infusion using bridging therapy might improve TME and potentiate CAR-T cell therapy. Here, we assessed the potential of poly (ADP-ribose) polymerase (PARP) inhibitors plus anlotinib as bridging therapy for CAR-T cells with resistance to TGFβ and capability of rapid expansion by bait-and-switch strategy of dual-targeting mesothelin (MSLN) and CD19 in preclinical models of advanced ovarian cancer. Methods: Immunocompetent mice bearing ID8 tumors were treated with niraparib (21 days) plus anlotinib (14 days) and euthanized at different timepoints (0, 7, or 14 days since discontinuation) to quantify tumor-infiltrating T cells and profile T cell functions. CAR-T cells transfected with dominant-negative TGFβRII dual-targeting MSLN and CD19 were produced by IASO Biotherapeutics. NSG mice bearing MSLN-positive cell- or patient-derived xenografts (CDX or PDX) of ovarian cancer received CAR-T cells alone or after bridging therapy (niraparib plus anlotinib followed by a wash-out period of 7 days). Tumor volume was balanced before CAR-T cell infusion. Replication-deficient NALM6 cells pre-treated with mitomycin C were injected to provide CD19 antigen. A PET scan that visualized granzyme B release was used to track CAR-T cells and assess immune-mediated tumor killing. Results: Niraparib combined with anlotinib increased tumor-infiltrating T cells without impairing T cell functionality. The effects of promoting T cell infiltration remained significant at 14 days after discontinuation, which might associate with lasting activation of cGAS-STING pathway and secretion of downstream chemokines (CXCL10 and CCL5), and normalized tumor vasculature featured by better perfusion and reduced leakage. The engineered CAR-T cells could resist TGFβ and displayed improved proliferation, cytotoxicity, cytokine release, and in vivo antitumor activities upon CD19 stimulation. Importantly, bridging therapy significantly increased CAR-T cell infiltration, curbed tumor growth, and prolonged survival in mice bearing SKOV3 CDX, HRD-negative PDX, and another multidrug-resistant PDX. PET imaging showed that bridging therapy increased tumor-infiltrating CAR-T cells and boosted tumor-killing capability. Conclusions: PARP inhibitors plus anlotinib as bridging therapy facilitated CAR-T cell infiltration and enhanced antitumor activities in multiple preclinical models of advanced ovarian cancer, and an early phase I trial (NCT05141253) is ongoing to evaluate PARP inhibitors plus anlotinib as bridging therapy for CAR-T cell therapy in patients with refractory MSLN-positive ovarian cancer. Citation Format: Huayi Li, Minghua Xiang, Jiahao Liu, Wei Mu, Li Zhu, Xuejiao Zhao, Gordon B. Mills, Qinglei Gao, Yong Fang. PARP inhibitors plus anlotinib as bridging therapy for TGFβ-insensitive CAR-T cell therapy targeting MSLN and CD19 in advanced ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3997.

Adoptive T cell therapy for solid tumors: current landscape and future challenges.

Adoptive cell therapy (ACT) comprises different strategies to enhance the activity of T lymphocytes and other effector cells that orchestrate the antitumor immune response, including chimeric antigen receptor (CAR) T-cell therapy, T-cell receptor (TCR) gene-modified T cells, and therapy with tumor-infiltrating lymphocytes (TILs). The outstanding results of CAR-T cells in some hematologic malignancies have launched the investigation of ACT in patients with refractory solid malignancies. However, certain characteristics of solid tumors, such as their antigenic heterogeneity and immunosuppressive microenvironment, hamper the efficacy of antigen-targeted treatments. Other ACT modalities, such as TIL therapy, have emerged as promising new strategies. TIL therapy has shown safety and promising activity in certain immunogenic cancers, mainly advanced melanoma, with an exciting rationale for its combination with immune checkpoint inhibitors. However, the implementation of TIL therapy in clinical practice is hindered by several biological, logistic, and economic challenges. In this review, we aim to summarize the current knowledge, available clinical results, and potential areas of future research regarding the use of T cell therapy in patients with solid tumors.

Efficacy and safety of stem cell therapy in patients with dilated cardiomyopathy: An umbrella review of systematic reviews.

Stem cell therapy (SCT) has emerged as a potential therapeutic avenue, with various cell types being explored for their efficacy in treating DCM. However, the safety and efficacy of these therapies have been the subject of numerous systematic reviews. This umbrella review aims to consolidate the existing evidence on stem cell interventions for DCM, providing a comprehensive overview of the current research landscape. This review was conducted following the JBI and PRISMA guidelines. Systematic reviews and meta-analyses of randomized controlled trials (RCTs) evaluating the safety and efficacy of SCT for DCM were included. Outcomes such as 6MWT, LVEDD, LVEF, MACE, NYHA, and QoL, among others, were considered. A literature search was executed across databases like PubMed, Embase, Web of Science, and Cochrane Database up to October 07, 2023. The quality of the included reviews was assessed using the JBI Checklist for Systematic Reviews and Research Syntheses. Data synthesis was carried out in both narrative and tabular formats, with the GRADE criteria guiding the determination of evidence certainty. Nine systematic reviews met the inclusion criteria. LVEF found to be significantly improved with SCT. LVEDD and LVEDV assessments yielded mixed results, with some reviews observing significant changes. LVESV showed consistent reductions across multiple studies. BNP concentrations post-interventions were explored in several studies, with mixed findings. Health-related quality of life (HRQL) showed varied results, with some studies noting improvements and others finding no significant differences. NYHA classifications and 6-MWT results indicated potential benefits from stem cell treatments. SCT was observed to be generally safe. The certainty of evidence was low or very low for most of outcomes. SCT showed has shown promise in treating DCM, with many studies highlighting its safety and potential benefits. Nonetheless, the existing data has its limitations due to biases in the RCTs studies. To truly establish the benefits of SCT for DCM, future high quality RCTS, are crucial.

Digital twins elucidate critical role of Tscm in clinical persistence of TCR-engineered cell therapy

Despite recent progress in adoptive T cell therapy for cancer, understanding and predicting the kinetics of infused T cells remains a challenge. Multiple factors can impact the distribution, expansion, and decay or persistence of infused T cells in patients. We have developed a novel quantitative systems pharmacology (QSP) model of TCR-transgenic T cell therapy in patients with solid tumors to describe the kinetics of endogenous T cells and multiple memory subsets of engineered T cells after infusion. These T cells undergo lymphodepletion, proliferation, trafficking, differentiation, and apoptosis in blood, lymph nodes, tumor site, and other peripheral tissues. Using the model, we generated patient-matched digital twins that recapitulate the circulating T cell kinetics reported from a clinical trial of TCR-engineered T cells targeting E7 in patients with metastatic HPV-associated epithelial cancers. Analyses of key parameters influencing cell kinetics and differences among digital twins identify stem cell-like memory T cells (Tscm) cells as an important determinant of both expansion and persistence and suggest that Tscm-related differences contribute significantly to the observed variability in cellular kinetics among patients. We simulated in silico clinical trials using digital twins and predict that Tscm enrichment in the infused product improves persistence of the engineered T cells and could enable administration of a lower dose. Finally, we verified the broader relevance of the QSP model, the digital twins, and findings on the importance of Tscm enrichment by predicting kinetics for two patients with pancreatic cancer treated with KRAS G12D targeting T cell therapy. This work offers insight into the key role of Tscm biology on T cell kinetics and provides a quantitative framework to evaluate cellular kinetics for future efforts in the development and clinical application of TCR-engineered T cell therapies.

CLDN18.2 chimeric antigen receptor T cell therapy for patients with advanced gastric and pancreatic adenocarcinoma: Results of ELIMYN18.2 phase 1b clinical trial.

356 Background: Autologous anti-claudin 18.2 (CLDN18.2) CAR T cell, satricabtagene autoleucel (satri-cel), was developed to treat solid tumors. We report the completed results of the Phase 1b ELIMYN18.2 study (Cohort A) in gastric/gastroesophageal junction (GC/GEJ) and pancreatic cancer (PC). Methods: This single-arm, open-label, Phase 1b/2 study (NCT04404595) evaluated the safety and efficacy of satri-cel in patients with CLDN18.2-positive advanced GC/GEJ or PC. Cohort A consisted of a modified 3+3 design. After a conditioning regimen of fludarabine, cyclophosphamide, and nab-paclitaxel, patients were administered 1-3 cycles of satri-cel. The primary objectives were safety and determination of the recommended Phase 2 dose (RP2D). Adverse Events (AEs) were graded per CTCAE 5.0, objective response rate (ORR), and clinical benefit rate (CBR) including CR, PR, and ≥6-month SD were assessed by the investigator per RECIST 1.1. Results: As of May 14, 2023, twenty-four patients underwent leukapheresis in Cohort A. Nineteen patients (7 GC/GEJ and 12 PC) with a median of 3 (range: 1-8) prior therapeutic lines had satri-cel at three dose levels (DLs) between 250×106 and 600×106 cells. Seven patients received a 2nd dose and two patients received a 3rd dose of satri-cel at a median of 113 and 259 days, respectively, post-first infusion. All 19 patients experienced at least one AE. No DLTs occurred and 17 patients experienced cytokine release syndrome (CRS). Two cases of Grade 3 CRS were reported, and all other CRS were Grade 1 or 2. Two Grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred. All CRS and ICANS were resolved. No severe gastrointestinal-related AEs were found. No increased toxicities were reported after any reinfusion. No satri-cel treatment-related death occurred. For all patients, the best ORR was 26.3%, the median DOR was 3.7 months and the CBR was 42.1%. The median PFS was 5.2 months, and overall survival was 12.8 months (95% CI 5.7-NE) after leukapheresis, and the median PFS was 3.3 months, and overall survival was 8.9 months (95% CI 3.3-NE) after the first infusion. In the GC/GEJ group, the ORR was 42.9% (3/7), the median DOR was 6.9 months and the CBR was 57.1%. In the PC group, the ORR was 16.7% (2/12), the median DOR was 3.4 months and the CBR was 33.3%. An ORR of 42.9% (3/7) and a CBR of 71.4% were reported at the DL3 of 600×106 cells which was selected as RP2D. At DL3, one GC patient achieved a CR and two PC patients had PR, suggesting the PC group achieved an ORR of 40% (2/5) and the GC group achieved an ORR of 50% (1/2). In addition, tumor shrinkage was detected in 73.7 % (14/19) of patients. Conclusions: The safety profile and therapeutic efficacy of satri-cel were shown to be promising in heavily pretreated patients with CLDN18.2-positive advanced GC/GEJ and PC . In the Phase 2 study, the first patient with GC received satri-cel in May 2023. Clinical trial information: NCT04404595 .

Safety and feasibility of anti-CD19 CAR T cells expressing inducible IL-7 and CCL19 in patients with relapsed or refractory large B-cell lymphoma

Although CD19-specific chimeric antigen receptor (CAR) T cells are curative for patients with relapsed or refractory large B-cell lymphoma (R/R LBCL), disease relapse with tumor antigen-positive remains a challenge. Cytokine/chemokine-expressing CAR-T cells could overcome a suppressive milieu, but the clinical safety and efficacy of this CAR-T therapy remain unclear. Here we report the preclinical development of CD19-specific CAR-T cells capable of expressing interleukin (IL)-7 and chemokine (C-C motif) ligand (CCL)-19 upon CD19 engagement (referred to as 7 × 19 CAR-T cells) and results from a phase 1 and expansion phase trial of 7 × 19 CAR-T cell therapy in patients with R/R LBCL (NCT03258047). In dose-escalation phase, there were no dose-limiting toxicities observed. 39 patients with R/R LBCL received 7 × 19 CAR-T with doses ranged from 0.5 × 106–4.0 × 106 cells per kg body weight. Grade 3 cytokine release syndrome occurred in 5 (12.8%) patients and ≥ grade 3 neurotoxicity in 4 (10.3%) patients. The overall response rate at 3 months post-single infusion was 79.5% (complete remission, 56.4%; partial response, 23.1%). With a median follow-up of 32 months, the median progression-free survival was 13 months, and median overall survival was not reached, with an estimated rate of 53.8% (95% CI, 40.3% to 72.0%) at two years. Together, these long-term follow-up data from the multicenter clinical study suggest that 7 × 19 CAR-T cells can induce durable responses with a median overall survival of greater than 2 years, and have a manageable safety profile in patients with R/R LBCL.

Identifying optimal candidates for autologous peripheral blood stem cell therapy in patients with decompensated liver cirrhosis: a prognostic scoring system.

Stem cell transplantation shows great potential to improve the long-term survival of cirrhosis patients. However, therapeutic effects may not be homogeneous across the whole study population. This study constructed an easy-to-use nomogram to improve prognostic prediction and aid in treatment decision making for cirrhotic patients. From August 2005 to April 2019, 315 patients with decompensated cirrhosis receiving autologous peripheral blood stem cell (PBSC) transplantation were enrolled in this study. They were randomly classified into training (2/3) and validation (1/3) groups. A predictive model was developed using Cox proportional hazard models and subsequently validated. The predictive performance of the model was evaluated and also compared with other prognostic models. Age, creatinine, neutrophil-to-lymphocyte ratio, and Child-Turcotte-Pugh class were included in the nomogram as prognostic variables. The nomogram showed high discrimination power concerning the area under receiver operating characteristic curves (3/5-year AUC: 0.742/0.698) and good consistency suggested by calibration plots. Patients could be accurately stratified into poor- and good-outcome groups regarding liver-transplantation free survival after receiving PBSC therapy (P < 0.001). Compared with poor-outcome group, the liver function of patients listed for liver transplantation in the good-outcome group was significantly improved (P < 0.001). Besides, our nomogram achieved a higher C-index (0.685, 95% CI 0.633-0.738) and better clinical utility compared with other conventional prognostic models. The proposed nomogram facilitated an accurate prognostic prediction for patients with decompensated cirrhosis receiving PBSC transplantation. Moreover, it also held the promise to stratify patients in clinical trials or practice to implement optimal treatment regimens for individuals.

Persistent Cytopenia After CD19 CAR T Therapy in Relapsed/Refractory DLBCL Patients Could Be a Predictor of Efficacy and Side Effects.

Hematological toxicity is a severe adverse event (AE) in anti-CD19 chimeric antigen receptor (CAR) T cell therapy for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, the pathophysiological mechanism underlying prolonged cytopenia and the relationship between persistent cytopenia, efficacy, and AEs after anti-CD19 CAR T cell therapy are unknown. Therefore, this study explored whether persistent cytopenia after anti-CD19 CAR T cell therapy in patients with R/R DLBCL can predict therapeutic efficacy and AEs. Thirty-eight patients with R/R DLBCL were enrolled in an anti-CD19 CAR T cell therapy clinical trial. Patients received lymphodepleting chemotherapy with fludarabine and cyclophosphamide before CAR T cell therapy. The degree and duration of cytopenia, clinical response, proportion of CAR T cells, interleukin-6 (IL-6) levels, AEs, and follow-up were observed after therapy. Grades 3-4 persistent cytopenia occurred in 14 patients with R/R DLBCL, who recovered 8-18 weeks after CAR T cell infusion. These patients achieved an objective response rate (ORR) for anti-CD19 CAR T cell therapy. In patients who achieved ORR, the incidence of Grades 3-4 persistent cytopenia was higher in patients with a high tumor load than in those without a high tumor load. The mean peaks of IL-6 and anti-CD19 CAR T cells and the cytokine release syndrome grade in patients with Grades 3-4 persistent cytopenia were higher than those in patients without persistent cytopenia. Anti-CD19 CAR T cells were observed 21 and 28 days after infusion, and patients had Grades 3-4 persistent cytopenia. Progression-free and overall survival were higher in patients with Grades 3-4 persistent cytopenia than in those without cytopenia. Therefore, persistent cytopenia after anti-CD19 CAR T cell therapy in patients with R/R DLBCL can predict therapeutic efficacy and AEs, allowing clinicians to determine the efficiency of CD-19 CAR T cell therapy and the associated AEs.

Phase I study targeting newly diagnosed grade 4 astrocytoma with bispecific antibody armed T cells (EGFR BATs) in combination with radiation and temozolomide

PurposeThe purpose of this study was to determine the safety, feasibility, and immunologic responses of treating grade 4 astrocytomas with multiple infusions of anti-CD3 x anti-EGFR bispecific antibody (EGFRBi) armed T cells (EGFR BATs) in combination with radiation and chemotherapy.MethodsThis phase I study used a 3 + 3 dose escalation design to test the safety and feasibility of intravenously infused EGFR BATs in combination with radiation and temozolomide (TMZ) in patients with newly diagnosed grade 4 astrocytomas (AG4). After finding the feasible dose, an expansion cohort with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) tumors received weekly EGFR BATs without TMZ.ResultsThe highest feasible dose was 80 × 109 EGFR BATs without dose-limiting toxicities (DLTs) in seven patients. We could not escalate the dose because of the limited T-cell expansion. There were no DLTs in the additional cohort of three patients with unmethylated MGMT tumors who received eight weekly infusions of EGFR BATs without TMZ. EGFR BATs infusions induced increases in glioma specific anti-tumor cytotoxicity by peripheral blood mononuclear cells (p < 0.03) and NK cell activity (p < 0.002) ex vivo, and increased serum concentrations of IFN-γ (p < 0.03), IL-2 (p < 0.007), and GM-CSF (p < 0.009).ConclusionTargeting AG4 with EGFR BATs at the maximum feasible dose of 80 × 109, with or without TMZ was safe and induced significant anti-tumor-specific immune responses. These results support further clinical trials to examine the efficacy of this adoptive cell therapy in patients with MGMT-unmethylated GBM.ClinicalTrials.gov Identifier: NCT03344250

Effectiveness of CAR-T cell therapy in patients with refractory and relapsed CD19-positive B-cell lymphomas

Effectiveness of CAR-T cell therapy in patients with refractory and relapsed CD19-positive B-cell lymphomas

Impact of Frailty on Outcomes after Chimeric Antigen Receptor T Cell Therapy for Patients with Relapsed/Refractory Multiple Myeloma

The literature is limited regarding outcomes in older adults and frail patients receiving BCMA-directed chimeric antigen receptor T cell therapy (CAR-T) for relapsed or refractory multiple myeloma. Here we describe the safety and efficacy of CAR-T in these clinically important subgroups treated in a real-world setting. Frailty was defined as a frail score ≥2 using the simplified frailty index (score based on age + Eastern Cooperative Oncology Group [ECOG] Performance Status + Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI]). Of the 136 patients analyzed (age range, 41 to 81 years), 83 (61%) were considered frail at the time of CAR-T infusion. Compared to the nonfrail group, the frail group had higher proportions of patients with renal insufficiency (18% versus 6%), high-risk cytogenetics (45% versus 35%), extramedullary disease (51% versus 43%), and ECOG Performance Status ≥2 (18% versus 2%), and worse HCT-CI (3 versus 1). Although patients in the frail group had a higher incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) (39% versus 17%), the incidences of all- grade cytokine release syndrome (CRS), as well as high-grade CRS and ICANS, were similar in the 2 groups. With a median follow-up of 7 months, the median progression-free survival was 6.9 months in the frail group versus 11.1 months in the nonfrail group (P = .028). The median overall survival was 14 months in the frail group and was not reached in the nonfrail group (P = .025). This study highlights the tolerable safety and reasonable efficacy of CAR-T for frail myeloma patients in a real-world practice. Although the frail patients did not experience any excessive high-grade toxicities, they did have inferior efficacy outcomes.

HTATIP2 regulates arteriogenic activity in monocytes from patients with limb ischemia.

Use of autologous cells isolated from elderly patients with multiple comorbidities may account for the modest efficacy of cell therapy in patients with chronic limb threatening ischemia (CLTI). We aimed to determine whether proarteriogenic monocyte/macrophages (Mo/MΦs) from patients with CLTI were functionally impaired and to demonstrate the mechanisms related to any impairment. Proarteriogenic Mo/MΦs isolated from patients with CLTI were found to have an impaired capacity to promote neovascularization in vitro and in vivo compared with those isolated from healthy controls. This was associated with increased expression of human HIV-1 TAT interactive protein-2 (HTATIP2), a transcription factor known to suppress angiogenesis/arteriogenesis. Silencing HTATIP2 restored the functional capacity of CLTI Mo/MΦs, which was associated with increased expression of arteriogenic regulators Neuropilin-1 and Angiopoietin-1, and their ability to enhance angiogenic (endothelial tubule formation) and arteriogenic (smooth muscle proliferation) processes in vitro. In support of the translational relevance of our findings, silencing HTATIP2 in proarteriogenic Mo/MΦs isolated from patients with CLTI rescued their capacity to enhance limb perfusion in the ischemic hindlimb by effecting greater angiogenesis and arteriogenesis. Ex vivo modulation of HTATIP2 may offer a strategy for rescuing the functional impairment of pro-angio/arteriogenic Mo/MΦs prior to autologous delivery and increase the likelihood of clinical efficacy.