A2B694 CAR T-Cells for Solid Cancers
(EVEREST-2 Trial)
Recruiting in Palo Alto (17 mi)
+13 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: A2 Biotherapeutics Inc.
Disqualifiers: Prior transplants, Cardiac disease, Lung disease, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial tests a new immune cell therapy for adults with difficult-to-treat solid tumors. The therapy modifies the patient's own immune cells to target and kill cancer cells while protecting healthy cells. The study aims to find a safe dose and see how well it works.
Do I need to stop my current medications to join the trial?
The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had cancer therapy within 3 weeks or 3 half-lives of the A2B694 infusion, and radiotherapy within 28 days of the infusion.
What data supports the effectiveness of the treatment A2B694 CAR T-Cells for Solid Cancers?
Research shows that using logic-gated CAR T-cells, like A2B694, can potentially improve the treatment of solid tumors by targeting multiple cancer markers and reducing side effects. This approach has shown promise in preclinical studies by enhancing the selectivity and effectiveness of the treatment.
12345What safety data exists for A2B694 CAR T-Cells for Solid Cancers?
The research articles provided do not contain specific safety data for A2B694 CAR T-Cells for solid cancers. They discuss safety in the context of other CAR T-cell therapies, primarily for blood cancers, noting issues like cytokine release syndrome and neurotoxicity, but these are not directly related to A2B694.
56789How is the A2B694 CAR T-Cell treatment different from other treatments for solid cancers?
The A2B694 CAR T-Cell treatment is unique because it uses a logic-gated Tmod CAR T-cell product, which is designed to improve the targeting of solid tumors by recognizing specific antigens on cancer cells, potentially overcoming the limitations of traditional CAR T-cell therapies that struggle with solid tumors.
910111213Eligibility Criteria
This trial is for adults with certain advanced solid tumors like colorectal, lung, pancreatic, ovarian cancer or mesothelioma. These cancers must express a protein called MSLN and lack HLA-A*02 due to mutation. Participants need measurable disease over 1 cm by CT scan, good organ function, an ECOG status of 0-1 (fully active to restricted in physically strenuous activity), and a life expectancy over 3 months.Inclusion Criteria
I am enrolled in the BASECAMP-1 study, my tests show LOH of HLA-A*02, and I have enough stored cells for Tmod CAR T-cell therapy.
My cancer is advanced, cannot be surgically removed, and shows MSLN.
I have completed the necessary treatment for my solid tumor as outlined.
+4 more
Exclusion Criteria
I need extra oxygen at home.
My condition can be treated with standard therapy aimed at curing, not just easing symptoms.
I have had lung conditions needing long-term steroids or immune suppressants in the past year.
+9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Preconditioning Lymphodepletion (PCLD) Regimen
Participants receive a preconditioning lymphodepletion regimen before the infusion of A2B694
1 week
Treatment
Participants receive a single dose of A2B694 intravenously on day 0
1 day
Follow-up
Participants are monitored for safety and effectiveness after treatment
24 months
Participant Groups
The study tests A2B694 CAR T-cell therapy after patients undergo preconditioning lymphodepletion. Phase 1 determines the safe dosage while Phase 2 checks if this dose effectively targets tumor cells without harming healthy ones. Patients previously enrolled in BASECAMP-1 are given A2B694 at the determined safe dose.
1Treatment groups
Experimental Treatment
Group I: A2B694Experimental Treatment2 Interventions
Patients receive Preconditioning Lymphodepletion (PCLD) Regimen followed by a single dose of A2B694 intravenously on day 0
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Mayo ClinicJacksonville, FL
Washington UniversitySt. Louis, MO
Fred Hutchinson Cancer CenterSeattle, WA
Banner HealthGilbert, AZ
More Trial Locations
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Who Is Running the Clinical Trial?
A2 Biotherapeutics Inc.Lead Sponsor
Tempus AIIndustry Sponsor
Tempus LabsIndustry Sponsor
References
To go or not to go? Biological logic gating engineered T cells. [2022]Genetically engineered T cells have been successfully used in the treatment of hematological malignancies, greatly increasing both progression-free and overall survival in patients. However, the outcomes of patients treated with Chimeric Antigen Receptor (CAR) T cells targeting solid tumors have been disappointing. There is an unmet clinical need for therapies which are specifically designed to overcome the challenges associated with solid tumors such as tumor heterogeneity and antigen escape. Genetic engineering employing the use of biological logic gating in T cells is an emerging and cutting-edge field that may address these issues. The advantages of logic gating include localized secretion of anti-tumor proteins into the tumor microenvironment, multi antigen targeting of tumors and a potential increase in safety when targeting tumor antigens which may not be exclusively tumor specific. In this review, we introduce the concept of biological logic gating and how this technology addresses some of the challenges of current CAR T treatment. We outline the types of logic gating circuits and finally discuss the application of this new technology to engineered T cells, in the treatment of cancer.
The Tmod cellular logic gate as a solution for tumor-selective immunotherapy. [2022]Immune cells that are engineered with receptors to integrate signals from multiple antigens offer a promising route to achieve the elusive property of therapeutic selectivity in cancer patients. Several types of multi-signal integrators have been described, among them mechanisms that pair activating and inhibitory receptors which are termed NOT gates by analogy to logical operations performed by machines. Here we review one such NOT-gated signal integrator called the Tmod system which is being developed for patients with solid tumors. Coupled with rigorous selection for patients with defined lesions in their tumor genomes (loss of heterozygosity), the Tmod approach presents an unusual opportunity to create truly selective therapies for certain cancer patients. Several of these agents are advancing toward the clinic, supported by a large body of quantitative preclinical data.
Co-opting signalling molecules enables logic-gated control of CAR T cells. [2023]Although chimeric antigen receptor (CAR) T cells have altered the treatment landscape for B cell malignancies, the risk of on-target, off-tumour toxicity has hampered their development for solid tumours because most target antigens are shared with normal cells1,2. Researchers have attempted to apply Boolean-logic gating to CAR T cells to prevent toxicity3-5; however, a truly safe and effective logic-gated CAR has remained elusive6. Here we describe an approach to CAR engineering in which we replace traditional CD3ζ domains with intracellular proximal T cell signalling molecules. We show that certain proximal signalling CARs, such as a ZAP-70 CAR, can activate T cells and eradicate tumours in vivo while bypassing upstream signalling proteins, including CD3ζ. The primary role of ZAP-70 is to phosphorylate LAT and SLP-76, which form a scaffold for signal propagation. We exploited the cooperative role of LAT and SLP-76 to engineer logic-gated intracellular network (LINK) CAR, a rapid and reversible Boolean-logic AND-gated CAR T cell platform that outperforms other systems in both efficacy and prevention of on-target, off-tumour toxicity. LINK CAR will expand the range of molecules that can be targeted with CAR T cells, and will enable these powerful therapeutic agents to be used for solid tumours and diverse diseases such as autoimmunity7 and fibrosis8. In addition, this work shows that the internal signalling machinery of cells can be repurposed into surface receptors, which could open new avenues for cellular engineering.
Robust In Vitro Pharmacology of Tmod, a Synthetic Dual-Signal Integrator for Cancer Cell Therapy. [2022]Progress toward improved solid-tumor treatment has long been hindered by the lack of truly tumor-specific targets. We have developed an approach to T cell therapy based on a dual-receptor system called Tmod™ that addresses this problem. The Tmod system exploits one of the few common genetic differences between tumor and normal cells: loss of heterozygosity (LOH). It utilizes the basic mechanistic logic that evolved in early vertebrates to mediate self vs. non-self discrimination, where an activation stimulus is blocked by self-ligands. Tmod constructs employ a chimeric antigen receptor (CAR) or T cell receptor (TCR) as activator component and a modified LIR-1 inhibitory receptor (blocker) to achieve high selectivity based on expression of the blocker antigen (Ag). Here we explore the in vitro pharmacology of a blocker directed at the HLA-A*02 Ag paired with either a mesothelin CAR or an HLA-A*11-restricted KRAS peptide TCR. While more sensitive to receptor expression changes on effector cells, we show that Tmod response is well-buffered against variations in Ag levels on target cells. In addition, the data reveal at least two distinguishable pharmacologic mechanisms of Tmod blocker function: (1) reducing activator sensitivity and (2) decreasing activation magnitude.
Multi-antigen-targeted chimeric antigen receptor T cells for cancer therapy. [2020]The approval of two chimeric antigen receptor-modified T cell types by the US Food and Drug Administration (FDA) for the treatment of hematologic malignancies is a milestone in immunotherapy; however, the application of CAR-T cells has been limited by antigen escape and on-target, off-tumor toxicities. Therefore, it may be a potentially effective strategy to select appropriate targets and to combine multi-antigen-targeted CAR-T cells with "OR", "AND" and "NOT" Boolean logic gates. We summarize the current limitations of CAR-T cells as well as the efficacy and safety of logic-gated CAR-T cells in antitumor therapy. This review will help to explore more optimized strategies to expand the CAR-T cell therapeutic window.
Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. [2022]Transitioning CD19-directed chimeric antigen receptor (CAR) T cells from early-phase trials in relapsed patients to a viable therapeutic approach with predictable efficacy and low toxicity for broad application among patients with high unmet need is currently complicated by product heterogeneity resulting from transduction of undefined T-cell mixtures, variability of transgene expression, and terminal differentiation of cells at the end of culture. A phase 1 trial of 45 children and young adults with relapsed or refractory B-lineage acute lymphoblastic leukemia was conducted using a CD19 CAR product of defined CD4/CD8 composition, uniform CAR expression, and limited effector differentiation. Products meeting all defined specifications occurred in 93% of enrolled patients. The maximum tolerated dose was 106 CAR T cells per kg, and there were no deaths or instances of cerebral edema attributable to product toxicity. The overall intent-to-treat minimal residual disease-negative (MRD-) remission rate for this phase 1 study was 89%. The MRD- remission rate was 93% in patients who received a CAR T-cell product and 100% in the subset of patients who received fludarabine and cyclophosphamide lymphodepletion. Twenty-three percent of patients developed reversible severe cytokine release syndrome and/or reversible severe neurotoxicity. These data demonstrate that manufacturing a defined-composition CD19 CAR T cell identifies an optimal cell dose with highly potent antitumor activity and a tolerable adverse effect profile in a cohort of patients with an otherwise poor prognosis. This trial was registered at www.clinicaltrials.gov as #NCT02028455.
A novel antibody-TCR (AbTCR) T-cell therapy is safe and effective against CD19-positive relapsed/refractory B-cell lymphoma. [2023]Label="PURPOSE" NlmCategory="OBJECTIVE">A barrier to widespread adoption of chimeric antigen receptor (CAR) T-cell therapy is toxicity. To address this, we recently developed a novel antibody-T-cell receptor (AbTCR) platform (trademarked as ARTEMIS®) which was designed to leverage natural immune receptor signaling and regulation. The AbTCR platform includes a gamma/delta (γδ) TCR-based AbTCR construct and a separate co-stimulatory molecule, both engineered to be tumor-specific. Here, we aim to assess the safety and preliminary efficacy of a CD19-directed AbTCR T-cell therapy.
Novel two-chain structure utilizing KIRS2/DAP12 domain improves the safety and efficacy of CAR-T cells in adults with r/r B-ALL. [2021]Engineered T cells that express chimeric antigen receptors (CARs) have been a promising therapy for hematologic malignancies. The optimization of CAR structure using different signaling domains can alter a wide range of CAR-T cell properties, including anti-tumor activity, long-term persistence, and safety. In this study, we developed a novel CAR structure based on KIRS2/Dap12 for B cell acute lymphoblastic leukemia (B-ALL) antigen CD19 and compared the anti-tumor efficacy and safety of this construct in transduced T cells with standard second-generation CAR-T cells targeting CD19 for B-ALL in vitro and in vivo and in adult relapsed/refractory (r/r) B-ALL patients. We discovered that KIRS2/Dap12 receptor infused with 4-1BB co-stimulation domain could enhance anti-tumor efficacy by remarkably increasing the production of pro-inflammatory interleukin-2 (IL-2), especially when co-cultured with antigen-positive tumor cells. In addition, CD19-KIRS2/Dap12-BB CAR-T cells showed the inspiring outcome that complete responses were seen in 4 of 4 (100%) patients without neurotoxicity and a high rate of severe cytokine release syndrome (CRS) after CAR-T infusion in a phase I clinical trial. Given these encouraging findings, CD19-KIRS2/Dap12-BB CAR-T cells are safe and can lead to clinical responses in adult patients with r/r B-ALL, indicating that further assessment of this therapy is warranted.
Engineering naturally occurring CD7- T cells for the immunotherapy of hematological malignancies. [2023]Chimeric antigen receptor (CAR) T-cell therapy targeting T-cell acute lymphoblastic leukemia (T-ALL) faces limitations such as antigen selection and limited T-cell persistence. CD7 is an attractive antigen for targeting T-ALL, but overlapping expression on healthy T cells leads to fratricide of CD7-CAR T cells, requiring additional genetic modification. We took advantage of naturally occurring CD7- T cells to generate CD7-CAR (CD7-CARCD7-) T cells. CD7-CARCD7- T cells exhibited a predominantly CD4+ memory phenotype and had significant antitumor activity upon chronic antigen exposure in vitro and in xenograft mouse models. Based on these encouraging results, we next explored the utility of CD7- T cells for the immunotherapy of CD19+ hematological malignancies. Direct comparison of nonselected (bulk) CD19-CAR and CD19-CARCD7- T cells revealed that CD19-CARCD7- T cells had enhanced antitumor activity compared with their bulk counterparts in vitro and in vivo. Lastly, to gain insight into the behavior of CD19-CAR T cells with low levels of CD7 gene expression (CD7lo) in humans, we mined single-cell gene and T-cell receptor (TCR) expression data sets from our institutional CD19-CAR T-cell clinical study. CD19-CARCD7lo T cells were present in the initial CD19-CAR T-cell product and could be detected postinfusion. Intriguingly, the only functional CD4+ CD19-CAR T-cell cluster observed postinfusion exhibited CD7lo expression. Additionally, samples from patients responsive to therapy had a higher proportion of CD7lo T cells than nonresponders (NCT03573700). Thus, CARCD7- T cells have favorable biological characteristics and may present a promising T-cell subset for adoptive cell therapy of T-ALL and other hematological malignancies.
Cancer immunotherapy with lymphocytes genetically engineered with T cell receptors for solid cancers. [2020]Adoptive transfer of T cells genetically engineered with chimeric antigen receptors (CAR-T cells) have proven to be highly effective for treating CD19+ B cell-derived hematologic malignancies. However, due to the lack of ideal tumor surface antigens, CAR-T cell therapy has limited success in treating solid tumors. T cells genetically engineered with T cell receptors (TCR-T cells) recognize intracellular and cell-surface antigens in the context of major histocompatibility complex (MHC) presentation and thus have the potential to access much more target antigens than CAR-T cells, providing great promise in treating solid tumors. There is an increasing interest in the application of TCR-T cell therapy for solid tumors, and fifty-six clinical trials are undergoing worldwide to confirm its validity. In this review, we summarize the recent progress in clinical studies of TCR-T cell therapy, describe strategies in the preparation and characterization of TCR-T cells, focusing on antigen selection, TCR isolation and methods to further enhance the potency of adoptively transferred cells.
[Development of Novel Gene-Modified T-Cell Therapies(CAR-T, TCR-T)]. [2023]In the 2000s, development of chimeric antigen receptor(CAR)gene transferred(modified)T-cell therapy(CAR-T)and cancer antigen-specific T-cell receptor gene transferred(modified)T-cell therapy(TCR-T)has been actively pursued. Since 2017, several CD19-CAR-T cell therapies have been approved for some CD19-positive B-cell lymphomas/leukemias, as well as CAR-T therapies targeting B-cell maturation antigen(BCMA)for multiple myeloma. However, CAR-T cell therapies are also being developed for solid tumors, but none are approved at this time. In addition, CAR-T cell therapies that recognize complexes of MHC and cancer antigen-derived peptides have recently been developed. This article reviews the development status and future challenges of gene-modified T-cell therapy for solid tumors.
TCR-T Immunotherapy: The Challenges and Solutions. [2022]T cell receptor-engineered T cell (TCR-T) therapy is free from the limit of surface antigen expression of the target cells, which is a potential cellular immunotherapy for cancer treatment. Significant advances in the treatment of hematologic malignancies with cellular immunotherapy have aroused the interest of researchers in the treatment of solid tumors. Nevertheless, the overall efficacy of TCR-T cell immunotherapy in solid tumors was not significantly high when compared with hematological malignancies. In this article, we pay attention to the barriers of TCR-T cell immunotherapy for solid tumors, as well as the strategies affecting the efficacy of TCR-T cell immunotherapy. To provide some reference for researchers to better overcome the impact of TCR-T cell efficiency in solid tumors.
Advances in CAR-T cell therapy for malignant solid tumors. [2023]T cells modified by chimeric antigen receptor (CAR) have the advantage of major histocompatibility complex-independent recognition of tumor-associated antigens, so can achieve efficient response to tumor targets. Chimeric antigen receptor (CAR) T cell therapy has shown a good therapeutic effect in hematological malignancies; however, its efficacy is generally not satisfactory for solid tumors. The reasons include the lack of tumor specific antigen target on solid tumors, the uncertainty of homing ability of engineered T cells and the inhibitory immune microenvironment of tumors. In clinical trials, the targets of CAR-T cell therapy for solid tumors are mainly disialoganglioside (GD2), claudin-18 isoform 2 (CLDN18.2), mesenchymal, B7 homolog 3 (B7H3), glypican (GPC) 3 and epidermal growth factor receptor variant Ш (EGFRvШ)Ⅲ. Combination of CAR-T cells with oncolytic viruses, tyrosine kinase inhibitors, and programmed death ligand-1 monoclonal antibodies may increase its efficacy. The CAR-T cell therapy for solid tumors can be optimized through gene editing to enhance the activity of CAR-T cells, adding corresponding regulatory components to make the activation of CAR-T cells safer and more controllable, and enhancing the persistence of CAR-T cells. In this article, we review the latest advances of CAR-T cell therapy in solid tumors to provide new insights for clinical application.