Cell Therapy Trials Research Articles

GOG-3084: A phase II trial of ADP-A2M4CD8 TCR-T cell therapy, alone or in combination with nivolumab, among patients with recurrent ovarian cancers

GOG-3084: A phase II trial of ADP-A2M4CD8 TCR-T cell therapy, alone or in combination with nivolumab, among patients with recurrent ovarian cancers

Clinical advances and challenges associated with TCR-T cell therapy for cancer treatment.

T cell receptor (TCR)-T cell therapy is an innovative form of cancer immunotherapy that genetically modifies patients' T cells to target and destroy cancer cells. However, the current status of clinical trials of TCR-T cell therapy for the treatment of cancer remains unclear. This study aimed to comprehensively analyze the registration trials related to TCR-T cell therapy for the treatment of cancer. A comprehensive search was conducted in the Trialtrove database for all clinical trials related to TCR-T cell therapy registered by August 1, 2024. Inclusion criteria focused on trials targeting TCR-T cell therapy for oncology, and excluded observational studies and incomplete data. Statistical analysis was performed on key trial characteristics, with between-group comparisons utilizing chi-square or Fisher's exact tests. Analysis of 174 eligible clinical trials revealed that TCR-T cell therapy exhibits significant efficacy across various tumor types, particularly in refractory hematologic malignancies and certain solid tumors. Additionally, combining TCR-T cell therapy with other immunotherapies enhanced these anti-tumor effects. TCR-T cell therapy holds substantial promise for cancer treatment. Future research should focus on optimizing treatment protocols, enhancing efficacy, and minimizing prices to fully realize the potential of this therapy.

Extracellular Microvesicles vs. Mitochondria: Competing for the Top Spot in Cardiovascular Regenerative Medicine.

Regenerative medicine aims to restore, replace, and regenerate human cells, tissues, and organs. Despite significant advancements, many cell therapy trials for cardiovascular diseases face challenges like cell survival and immune compatibility, with benefits largely stemming from paracrine effects. Two promising therapeutic tools have been recently emerged in cardiovascular diseases: extracellular vesicles (EVs) and mitochondrial transfer. Concerning EVs, the first pivotal study with EV-enriched secretome derived from cardiovascular progenitor cells has been done treating heart failure. This first in man demonstrated the safety and feasibility of repeated intravenous infusions and highlighted significant clinical improvements, including enhanced cardiac function and reduced symptoms in heart failure patients. The second study uncovered a novel mechanism of endothelial regeneration through mitochondrial transfer via tunneling nanotubes (TNTs). This research showed that mesenchymal stromal cells (MSCs) transfer mitochondria to endothelial cells, significantly enhancing their bioenergetics and vessel-forming capabilities. This mitochondrial transfer was crucial for endothelial cell engraftment and function, offering a new strategy for vascular regeneration without the need for additional cell types. Combining EV and mitochondrial strategies presents new clinical opportunities. These approaches could revolutionize regenerative medicine, offering new hope for treating cardiovascular and other degenerative diseases. Continued research and clinical trials will be crucial in optimizing these therapies, potentially leading to personalized medicine approaches that enhance patient outcomes.

Updates for newly diagnosed and recurrent glioblastoma: a review of recent clinical trials.

Glioblastoma (GBM) is the most common and devastating primary malignant brain tumor. We summarize recent advances in radiotherapy, immunotherapy, and targeted therapy approaches for the treatment of newly diagnosed and recurrent glioblastoma. We also introduce ongoing clinical trials. Recent clinical trials have explored multiple novel strategies to treat GBM including the use of oncoviruses, chimeric antigen receptor (CAR) T cell therapy, vaccines, radiotherapy, and novel drug delivery techniques to improves drug penetrance across the blood brain barrier. Approaches to improve drug delivery to brain tumors have the potential to expand treatment options of existing therapies that otherwise have poor brain tumor penetrance. Immunotherapy has been of keen interest in both newly diagnosed and recurrent glioblastoma. Vaccines SurVaxM and DCVax-L have shown initial promise in phase II and III trials, respectively. CAR T cell therapy trials are in their early phases but hold promise in both newly diagnosed and recurrent glioblastoma. Although progress to improve outcomes for GBM patients has been modest, multiple novel strategies utilizing combination therapies, focused ultrasound to improve drug delivery, and novel immunotherapies are underway.

Gemcitabine, carboplatin, and Epstein–Barr virus-specific autologous cytotoxic T lymphocytes for recurrent or metastatic nasopharyngeal carcinoma: VANCE, an international randomized phase III trial

Epstein-Barr virus-specific cytotoxic T lymphocyte (EBV-CTL) is an autologous adoptive T-cell immunotherapy generated from the blood of individuals and manufactured without genetic modification. In a previous phase II trial of locally recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) patients, first-line gemcitabine and carboplatin (GC) and EBV-CTL combination demonstrated objective antitumor EBV-CTL activity and a favorable safety profile. The present study explored whether this combined first-line chemo-immunotherapy strategy would produce superior clinical efficacy and better quality of life compared with conventional chemotherapy treatment. This multicenter, randomized, phase III trial evaluated the efficacy and safety of GC followed by EBV-CTL versus GC alone as first-line treatment of R/M NPC patients. Thirty clinical sites in Singapore, Malaysia, Taiwan, Thailand, and the USA were included. Subjects were randomized to first-line GC (four cycles) and EBV-CTL (six cycles) or GC (six cycles) in a 1 : 1 ratio. The primary outcome was overall survival (OS) and secondary outcomes included progression-free survival, objective response rate, clinical benefit rate, quality of life, and safety. gov identifier: NCT02578641. A total of 330 subjects with NPC were enrolled. Most subjects in both treatment arms received four or more cycles of chemotherapy and most subjects in the GC+ EBV-CTL group received two or more infusions of EBV-CTL. The central Good Manufacturing Practices (GMP) facility produced sufficient EBV-CTL for 94% of GC+ EBV-CTL subjects. The median OS was 25.0 months in the GC+ EBV-CTL group and 24.9 months in the GC group (hazard ratio= 1.19; 95% confidence interval 0.91-1.56; P= 0.194). Only one subject experienced a grade 2 serious adverse event related to EBV-CTL. GC+ EBV-CTL in subjects with R/M NPC demonstrated a favorable safety profile but no overall improvement in OS versus chemotherapy. This is the largest adoptive T-cell therapy trial reported in solid tumors to date.

LIM-domain-only 4 (LMO4) enhances CD8+ T-cell stemness and tumor rejection by boosting IL-21-STAT3 signaling

High frequencies of stem-like memory T cells in infusion products correlate with superior patient outcomes across multiple T cell therapy trials. Herein, we analyzed a published CRISPR activation screening to identify transcriptional regulators that could be harnessed to augment stem-like behavior in CD8+ T cells. Using IFN-γ production as a proxy for CD8+ T cell terminal differentiation, LMO4 emerged among the top hits inhibiting the development of effectors cells. Consistently, we found that Lmo4 was downregulated upon CD8+ T cell activation but maintained under culture conditions facilitating the formation of stem-like T cells. By employing a synthetic biology approach to ectopically express LMO4 in antitumor CD8+ T cells, we enabled selective expansion and enhanced persistence of transduced cells, while limiting their terminal differentiation and senescence. LMO4 overexpression promoted transcriptional programs regulating stemness, increasing the numbers of stem-like CD8+ memory T cells and enhancing their polyfunctionality and recall capacity. When tested in syngeneic and xenograft tumor models, LMO4 overexpression boosted CD8+ T cell antitumor immunity, resulting in enhanced tumor regression. Rather than directly modulating gene transcription, LMO4 bound to JAK1 and potentiated STAT3 signaling in response to IL-21, inducing the expression of target genes (Tcf7, Socs3, Junb, and Zfp36) crucial for memory responses. CRISPR/Cas9-deletion of Stat3 nullified the enhanced memory signature conferred by LMO4, thereby abrogating the therapeutic benefit of LMO4 overexpression. These results establish LMO4 overexpression as an effective strategy to boost CD8+ T cell stemness, providing a new synthetic biology tool to bolster the efficacy of T cell-based immunotherapies.

Abstract Mo130: Epigenetic Mechanisms Regulate Sex Differences in Cardiac Reparative Functions of Bone Marrow Progenitor Cells

Historically, lower incidence of CVD and related deaths in women as compared with men of the same age has been attributed to female sex hormones, particularly estrogen and its receptors. Autologous Bone marrow stem cell (BMSC) clinical trials for cardiac cell therapy overwhelmingly included male patients; however, meta-analysis data on these trials suggest a better functional outcome in women as compared with men. A direct comparison of the mechanisms governing sex-specific cardiac reparative activity in bone marrow-derived mesenchymal stem cells (BMSCs), with and without the influence of sex hormones, remains unexplored. This study was designed to identify mechanisms that regulate superior reparative properties of female endothelial progenitor cells (EPCs) post-MI, particularly epigenetic mechanisms. Male (M), female (F), and ovariectomized female (OVX) mice-derived EPCs were subjected to a series of molecular and epigenetic analyses followed by in vivo functional assessments of cardiac repair. RNA sequencing and other quantitative assays showed a similar genetic profile between F-EPCs and OVX-EPCs, distinct from M-EPCs that displayed significant up-regulation of inflammation-related genes. F-EPCs and OVX EPCs secrete higher levels of proangiogenic factors, lower levels of proinflammatory cytokines and show better cardiac reparative activity after intra-cardiac injections in a male mouse model of myocardial infarction (MI). Epigenetic sequencing revealed a marked difference in the occupancy of the gene repressive H3K9me3 mark, particularly at transcription start sites of key angiogenic and proinflammatory genes in male EPCs compared with female and ovariectomized EPCs. Our study unveiled that functional sex differences in EPCs is, in part, mediated by differential epigenetic regulation of the proinflammatory and anti-angiogenic gene CCL3, orchestrated by the control of H3K9me3 by histone methyltransferase, G9a/Ehmt2. Our research highlights the importance of considering sex of donor cells for progenitor-based tissue repair.

A systematic review of cell therapy modalities and outcomes in cerebral palsy.

Cerebral palsy is widely recognized as a condition that results in significant physical and cognitive disabilities. Interventions aim to improve the quality of life and reduce disability. Despite numerous treatments and significant advancements, cerebral palsy remains incurable due to its diverse origins. This review evaluated clinical trials, studies, and case reports on various cell therapy approaches for cerebral palsy. It assessed the clinical outcomes of applying different cell types, including mesenchymal stem cells, olfactory ensheathing cells, neural stem/progenitor cells, macrophages, and mononuclear cells derived from peripheral blood, cord blood, and bone marrow. In 60 studies involving 1474CP patients, six major adverse events (0.41%) and 485 mild adverse events (32.9%) were reported. Favorable therapeutic effects were observed in 54 out of 60 cell therapy trials, indicating a promising potential for cell treatments in cerebral palsy. Intrathecal MSC and BM-MNC applications revealed therapeutic benefits, with MSC studies being generally safer than other cell therapies. However, MSC and BM-MNC trials have shown inconsistent results, with some demonstrating superior efficacy for certain outcomes. Cell dosage, transplantation route, and frequency of administration can affect the efficacy of these therapies. Our findings highlight the promise of cell therapies for improving cerebral palsy treatment and stress the need for ongoing research to refine treatment protocols and enhance safety. To establish conclusive evidence on the comparative effectiveness of various cell types in treating cerebral palsy, randomized, double-blind clinical trials are essential.

Comparative effectiveness of mesenchymal stem cell versus bone-marrow mononuclear cell transplantation in heart failure: a meta-analysis of randomized controlled trials

BackgroundThere is no clear evidence on the comparative effectiveness of bone-marrow mononuclear cell (BMMNC) vs. mesenchymal stromal cell (MSC) stem cell therapy in patients with chronic heart failure (HF).MethodsUsing a systematic approach, eligible randomized controlled trials (RCTs) of stem cell therapy (BMMNCs or MSCs) in patients with HF were retrieved to perform a meta-analysis on clinical outcomes (major adverse cardiovascular events (MACE), hospitalization for HF, and mortality) and echocardiographic indices (including left ventricular ejection fraction (LVEF)) were performed using the random-effects model. A risk ratio (RR) or mean difference (MD) with corresponding 95% confidence interval (CI) were pooled based on the type of the outcome and subgroup analysis was performed to evaluate the potential differences between the types of cells.ResultsThe analysis included a total of 36 RCTs (1549 HF patients receiving stem cells and 1252 patients in the control group). Transplantation of both types of cells in patients with HF resulted in a significant improvement in LVEF (BMMNCs: MD (95% CI) = 3.05 (1.11; 4.99) and MSCs: MD (95% CI) = 2.82 (1.19; 4.45), between-subgroup p = 0.86). Stem cell therapy did not lead to a significant change in the risk of MACE (MD (95% CI) = 0.83 (0.67; 1.06), BMMNCs: RR (95% CI) = 0.59 (0.31; 1.13) and MSCs: RR (95% CI) = 0.91 (0.70; 1.19), between-subgroup p = 0.12). There was a marginally decreased risk of all-cause death (MD (95% CI) = 0.82 (0.68; 0.99)) and rehospitalization (MD (95% CI) = 0.77 (0.61; 0.98)) with no difference among the cell types (p > 0.05).ConclusionBoth types of stem cells are effective in improving LVEF in patients with heart failure without any noticeable difference between the cells. Transplantation of the stem cells could not decrease the risk of major adverse cardiovascular events compared with controls. Future trials should primarily focus on the impact of stem cell transplantation on clinical outcomes of HF patients to verify or refute the findings of this study.

Progress and pitfalls of gene editing technology in CAR-T cell therapy: a state-of-the-art review.

CAR-T cell therapy has shown remarkable promise in treating B-cell malignancies, which has sparked optimism about its potential to treat other types of cancer as well. Nevertheless, the Expectations of CAR-T cell therapy in solid tumors and non-B cell hematologic malignancies have not been met. Furthermore, safety concerns regarding the use of viral vectors and the current personalized production process are other bottlenecks that limit its widespread use. In recent years the use of gene editing technology in CAR-T cell therapy has opened a new way to unleash the latent potentials of CAR-T cell therapy and lessen its associated challenges. Moreover, gene editing tools have paved the way to manufacturing CAR-T cells in a fully non-viral approach as well as providing a universal, off-the-shelf product. Despite all the advantages of gene editing strategies, the off-target activity of classical gene editing tools (ZFNs, TALENs, and CRISPR/Cas9) remains a major concern. Accordingly, several efforts have been made in recent years to reduce their off-target activity and genotoxicity, leading to the introduction of advanced gene editing tools with an improved safety profile. In this review, we begin by examining advanced gene editing tools, providing an overview of how these technologies are currently being applied in clinical trials of CAR-T cell therapies. Following this, we explore various gene editing strategies aimed at enhancing the safety and efficacy of CAR-T cell therapy.

Phase I trial of hypoxia-responsive CEA CAR-T cell therapy in patients with heavily pretreated solid tumor via intraperitoneal or intravenous transfusion.

3514 Background: Chimeric antigen receptor (CAR) T cell therapy has been successful in hematologic malignancies but not in solid tumors. Homing capacity and tumor microenvironment are key issues to limit CAR-T efficacy to solid tumors. Our previous study has shown that hypoxia-responsive CAR-T cells exhibit reduced exhaustion and enhanced efficacy in solid tumors (Cancer Res 2024). Here, we aimed to optimize the administration route by comparing safety and efficacy of our newly established CEA CAR-T through intraperitoneal (I.P.) and intravenous (I.V.) infusions in solid tumor patients who failed to standard therapy. Methods: In this phase I, open-label, dose-escalation clinical trial, eligible patients were CEA positive and relapsed or refractory to at least second-line treatment. CAR-T cells was administered via I.P. or I.V. with dose escalation including low dose of 1-3 x106 CAR+/kg and high dose of 4-6 x106 CAR+/kg. Adverse events were graded by CTCAE 5.0. Tumor responses were evaluated using RECIST 1.1. Results: Between June 2022 to Jan 2024,40 pts were enrolled and infused CAR-T cells, including 35 CRC pts, 3 GC pts, 1 NSCLC pts and 1 BTC pts. There were 16 pts in the I.P. group and 24 pts in the I.V. group. CRS was observed in 62.5% of the pts at grade 1-2, and no ICANS or treatment related death was reported. Grade 1-2 mucositis was reported in 25% of the patients. Immune-mediated diarrhea and colitis of all grades occurred in 32.5% of the patients, including 17.5% grade 3 events. And 100% of patients experienced grade 3-4 hematologic toxicity. In terms of efficacy, the I.P. group displayed a higher objective response rate (ORR) of 25% (4/16), compared to 8% (2/24) in the I.V. group, alongside a superior disease control rate (DCR) of 88% (14/16) in I.P. compared to 67% (16/24) in I.V. group. Notably, within the high-dose group receiving I.P. infusion, the ORR increased to 28.5%. Moreover, the responded patients in the high-dose group all had sustained tumor remission for more than 5 months, including one patient who had a 76% target lesions regression at six months follow up. CAR-T cells demonstrated robust expansion in both the I.P. and I.V. groups, while no significant difference was found in maximum concentration. Conclusions: The CEA CAR-T cell therapy had acceptable toxicity via I.P. or I.V. infusion. We have observed a promising antitumor potential by I.P. infusion and a prolonged tumor remission in high-dose group. Further investigation is needed to highlight these findings and the corresponding mechanisms. Clinical trial information: NCT05396300 . [Table: see text]

Human MuStem cells are competent to fuse with nonhuman primate myofibers in a clinically relevant transplantation context: A proof-of-concept study.

We previously reported that human muscle-derived stem cells (hMuStem cells) contribute to tissue repair after local administration into injured skeletal muscle or infarcted heart in immunodeficient rodent models. However, extrapolation of these findings to a clinical context is problematic owing to the considerable differences often seen between in vivo findings in humans versus rodents. Therefore, we investigated whether the muscle regenerative behavior of hMuStem cells is maintained in a clinically relevant transplantation context. Human MuStem cells were intramuscularly administered by high-density microinjection matrices into nonhuman primates receiving tacrolimus-based immunosuppression thereby reproducing the protocol that has so far produced the best results in clinical trials of cell therapy in myopathies. Four and 9 weeks after administration, histological analysis of cell injection sites revealed large numbers of hMuStem cell-derived nuclei in all cases. Most graft-derived nuclei were distributed in small myofiber groups in which no signs of a specific immune response were observed. Importantly, hMuStem cells contributed to simian tissue repair by fusing mainly with host myofibers, demonstrating their capacity for myofiber regeneration in this model. Together, these findings obtained in a valid preclinical model provide new insights supporting the potential of hMuStem cells in future cell therapies for muscle diseases.

Multiple treatment interruptions and protecting HIV-specific CD4 T cells enable durable CD8 T cell response and viral control.

Human Immunodeficiency Virus (HIV) remains a global health challenge, and novel approaches to improve HIV control are significantly important. The cell and gene therapy product AGT103-T was previously evaluated (NCT04561258) for safety, immunogenicity, and persistence in seven patients for up to 180 days post infusion. In this study, we sought to investigate the impact of AGT103-T treatment upon analytical treatment interruptions (ATIs). Six patients previously infused with AGT103-T were enrolled into an ATI study (NCT05540964), wherein they suspended their antiretroviral therapy (ART) until their viral load reached 100,000 copies/mL in two successive visits, or their CD4 count was reduced to below 300 cells/μL. During the ATI, all patients experienced viral rebound followed by a notable expansion in HIV specific immune responses. The participants demonstrated up to a five-fold increase in total CD8 counts over baseline approximately 1-2 weeks followed by the peak viremia. This coincided with a rise in HIV-specific CD8 T cells, which was attributed to the increase in antigen availability and memory recall. Thus, the protocol was amended to include a second ATI with the first ATI serving as an "auto-vaccination." Four patients participated in a second ATI. During the second ATI, the Gag-specific CD8 T cells were either maintained or rose in response to viral rebound and the peak viremia was substantially decreased. The patients reached a viral set point ranging from 7,000 copies/mL to 25,000 copies/mL. Upon resuming ART, all participants achieved viral control more rapidly than during the first ATI, with CD4 counts remaining within 10% of baseline measurements and without any serious adverse events or evidence of drug resistance. In summary, the rise in CD8 counts and the viral suppression observed in 100% of the study participants are novel observations demonstrating that AGT103-T gene therapy when combined with multiple ATIs, is a safe and effective approach for achieving viral control, with viral setpoints consistently below 25,000 copies/mL and relatively stable CD4 T cell counts. We conclude that HIV cure-oriented cell and gene therapy trials should include ATI and may benefit from designs that include multiple ATIs when induction of CD8 T cells is required to establish viral control.

Safety and biological outcomes following a phase 1 trial of GD2-specific CAR-T cells in patients with GD2-positive metastatic melanoma and other solid cancers

BackgroundChimeric antigen receptor (CAR) T cell therapies specific for the CD19 and B-cell maturation antigen have become an approved standard of care worldwide for relapsed and refractory B-cell malignancies. If...

International Society for Cell and Gene Therapy Clinical Translation Committee recommendations on mesenchymal stromal cells in graft-versus-host disease: easy manufacturing is faced with standardizing and commercialization challenges

Mesenchymal stromal cells (MSCs) have been used in multiple clinical trials for steroid-refractory moderate-severe (grade II–IV) acute graft-versus-host disease (aGVHD) across the world over the last two decades. Despite very promising results in a variety of trials, it failed to get widespread approval by regulatory agencies such as the U.S. Food and Drug Administration and the European Medicines Agency. What lessons can we learn from this for future studies on MSCs and other cell therapy products? Broad heterogeneity among published trials using MSCs in aGVHD was likely the core problem. We propose a standardized approach in regards to donor-related factors, MSCs-related characteristics, as well as clinical trial design, to limit heterogeneity in trials for aGVHD and to fulfill the requirements of regulatory agencies. This approach may be expanded beyond MSCs to other Cell and Gene therapy products and trials in other diseases.

Epigenetic mechanisms regulate sex differences in cardiac reparative functions of bone marrow progenitor cells

Historically, a lower incidence of cardiovascular diseases (CVD) and related deaths in women as compared with men of the same age has been attributed to female sex hormones, particularly estrogen and its receptors. Autologous bone marrow stem cell (BMSC) clinical trials for cardiac cell therapy overwhelmingly included male patients. However, meta-analysis data from these trials suggest a better functional outcome in postmenopausal women as compared with aged-matched men. Mechanisms governing sex-specific cardiac reparative activity in BMSCs, with and without the influence of sex hormones, remain unexplored. To discover these mechanisms, Male (M), female (F), and ovariectomized female (OVX) mice-derived EPCs were subjected to a series of molecular and epigenetic analyses followed by in vivo functional assessments of cardiac repair. F-EPCs and OVX EPCs show a lower inflammatory profile and promote enhanced cardiac reparative activity after intra-cardiac injections in a male mouse model of myocardial infarction (MI). Epigenetic sequencing revealed a marked difference in the occupancy of the gene repressive H3K9me3 mark, particularly at transcription start sites of key angiogenic and proinflammatory genes in M-EPCs compared with F-EPCs and OVX-EPCs. Our study unveiled that functional sex differences in EPCs are, in part, mediated by differential epigenetic regulation of the proinflammatory and anti-angiogenic gene CCL3, orchestrated by the control of H3K9me3 by histone methyltransferase, G9a/Ehmt2. Our research highlights the importance of considering the sex of donor cells for progenitor-based tissue repair.

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.

First-in-Human Trial of NRTX-1001 GABAergic Interneuron Cell Therapy for Treatment of Focal Epilepsy - Emerging Clinical Trial Results (S19.002)

First-in-Human Trial of NRTX-1001 GABAergic Interneuron Cell Therapy for Treatment of Focal Epilepsy - Emerging Clinical Trial Results (S19.002)

PD-1 downregulation enhances CAR-T cell antitumor efficiency by preserving a cell memory phenotype and reducing exhaustion

BackgroundDespite the encouraging outcome of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) in managing relapsed or refractory multiple myeloma (RRMM) patients, the therapeutic side effects...

Abstract 3636: Myeloid cell rebound associated with GD2-CAR-T cell therapy in solid tumor patients

Abstract GD2 is a validated cancer immunotherapy target with highly restricted normal tissue expression. Promising activity of GD2-CAR-T cell therapy in diffuse midline glioma and neuroblastoma has promoted interest in this therapy. We initiated three phase 1 clinical trials of escalating doses of intravenously administered autologous GD2-CAR-T cells in patients with advanced GD2-positive solid tumors. Emerging evidence suggests that CAR-T cells may increase circulating myeloid derived suppressor cells (MDSCs) and that this event may be mediated and/or triggered by CAR-T cell-derived cytokines and chemokines. These findings may help to explain the limited persistence of CAR-T cell therapy in solid tumor patients. Hence, we sought evidence of MDSC generation and secretion of relevant cytokines and chemokines in our clinical trial patients. The CARPETS trial (www.anzctr.org.au: ACTRN12620000622909) recently closed to recruitment after enrolling 12 patients (7 melanoma, 4 colorectal cancer, and 1 sarcoma). No significant adverse events were attributable to CAR-T cell therapy. We opened two other GD2-CAR-T cell therapy trials in 2023: LEVI’S-CATCH (ACTRN12622000675729) in patients with diffuse midline glioma at Sydney Children’s Hospital and KARPOS (ACTRN12622001514796) in adult patients with recurrent glioblastoma at Royal Adelaide Hospital. To date, 3 patients have enrolled to LEVI’S-CATCH with the first patient clearing the dose limiting (DLT) evaluation period. Three patients completed enrolment to the first dose cohort of KARPOS without DLTs. In all CARPETS patients, CAR-T cell expansion, which was measured by by DNA quantitative PCR and flow cytometry, peaked during the 6-week post-CAR-T infusion DLT evaluation period. In 6 CARPETS patients for whom peripheral blood samples were available, we found by flow cytometry, newly formed or increased size of pre-existing subpopulations of non-classical monocytes and/or MDSCs of mononuclear and/or polymorphonuclear class, which peaked at or after the time of peak CAR-T cell expansion. Typically, serum levels of inflammatory cytokines and chemokines such as TNF, IL-6, IL-8, CCL2, GM-CSF, and CXCL10, were detected only after the CAR-T cell infusion with variable patterns of the timing and concentration of analyte observed among the 12 patients. At the time of writing, blood samples from the first KARPOS patient showed CAR-T cell expansion and the subsequent increases in circulating myeloid derived suppressor cells and inflammatory cytokines. We expect that full data sets for these parameters will be presented for current and future enrolled patients to both studies. To improve CAR-T cell persistence in solid tumor patients, these data indicate the need for new therapeutic strategies to mitigate effects of CAR-T cell induced myeloid cells with antitumor activity. Citation Format: Michael P. Brown, Tessa Gargett, Nga T. Truong, Orazio Vittorio, David S. Ziegler. Myeloid cell rebound associated with GD2-CAR-T cell therapy in solid tumor patients [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 3636.