Engineered T-Cell Therapy for Cancer
Recruiting in Palo Alto (17 mi)
+8 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: AstraZeneca
Must not be taking: Immunosuppressants, Aminoglycosides
Disqualifiers: CNS malignancy, Cardiac disease, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial tests NT-175, a personalized treatment made from a patient's own immune cells, in patients with advanced cancers that have a specific genetic mutation. The treatment works by enhancing the immune system to attack cancer cells.
Will I have to stop taking my current medications?
The trial requires that you stop any systemic therapy at least 2 weeks or 3 half-lives (whichever is shorter) before enrolling. This means you may need to stop certain medications before participating.
What data supports the effectiveness of the treatment NT-175 for cancer?
Research shows that engineered T cells, like those used in NT-175, have shown promise in targeting and killing cancer cells. Studies have demonstrated that these T cells can be modified to specifically attack cancer cells, leading to tumor regression in some patients.
12345Is engineered T-cell therapy generally safe for humans?
Engineered T-cell therapies, like CAR T cells and TCR T cells, have shown promise in treating certain cancers, but they can also cause side effects such as cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). Clinical trials have identified these safety concerns, and ongoing research aims to balance effective cancer targeting with minimizing harm to normal tissues.
26789What makes the NT-175 treatment unique for cancer?
NT-175 is unique because it involves engineered T cells that are genetically modified to specifically target and kill cancer cells, potentially offering a more precise and effective treatment compared to traditional therapies. This approach can also help the immune system remember and continue fighting cancer over time.
110111213Eligibility Criteria
Adults over 18 with advanced solid tumors positive for HLA-A*02:01 and TP53 R175H mutation, who've tried standard treatments without cure. Eligible cancers include NSCLC, colorectal adenocarcinoma, head and neck squamous cell carcinoma, pancreatic adenocarcinoma, breast cancer or other solid tumors. Must have measurable disease and be in good physical condition.Inclusion Criteria
I have been diagnosed with a specific type of cancer, such as lung, colon, head and neck, pancreatic, breast, or another solid tumor.
I am able to understand and sign the consent form.
Subject has at least 1 measurable lesion per computed tomography (CT) scan or magnetic resonance imaging (MRI)
+6 more
Exclusion Criteria
I have not had serious heart problems or heart failure in the last 6 months.
I have Li-Fraumeni syndrome or a relative diagnosed with it.
I haven't had any systemic therapy for at least 2 weeks or 3 half-lives, whichever is shorter.
+9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Escalation
Investigate escalating doses of NT-175 to evaluate safety and determine the maximum tolerated dose (MTD)
Up to 24 months
Disease Histology Evaluation
Evaluate safety and preliminary anti-tumor activity at or below the MTD in specific disease histologies
Up to 24 months
Disease Cohort Expansion
Further evaluate the preliminary anti-tumor activity and safety of NT-175 at the recommended phase 2 dose (RP2D) in disease-specific settings
Up to 24 months
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 24 months
Participant Groups
The trial is testing NT-175 T cells engineered to target the TP53 R175H mutation in various advanced solid tumors. It's a Phase I study assessing safety and how well these modified T cells work against the cancer.
3Treatment groups
Experimental Treatment
Group I: Part 2: Disease Cohort ExpansionExperimental Treatment1 Intervention
TCR T Cell Product at the RP2D
Group II: Part 1: Disease Histology EvaluationExperimental Treatment1 Intervention
TCR T Cell Product at the MTD
Group III: Dose Escalation and ExpansionExperimental Treatment1 Intervention
Dose Escalation of TCR T cell product
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Sarah Cannon Research Institute (SCRI) Oncology PartnersNashville, TN
Baylor Scott & White Medical CenterDallas, TX
Providence Cancer InstitutePortland, OR
MD Anderson Cancer CenterHouston, TX
More Trial Locations
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Who Is Running the Clinical Trial?
AstraZenecaLead Sponsor
Neogene Therapeutics, Inc.Lead Sponsor
References
Muscle CARs and TcRs: turbo-charged technologies for the (T cell) masses. [2012]A central role for T cells in the control of cancer has been supported by both animal models and clinical observations. Accordingly, the development of potent anti-tumor T cell immunity has been a long-standing objective of immunotherapy. Emerging data from clinical trials that test T cell immune-modulatory agents and genetically engineered and re-targeted T cells have begun to realize the profound potential of T cell immunotherapy to target cancer. This review will focus on a description of recent conceptual and technological advances for the genetic engineering of T cells to enhance anti-tumor T cell immunity through the introduction of tumor-specific receptors, both Chimeric Antigen Receptors (CAR) and T cell receptors (TcR), as well as an overview of emerging data from ongoing clinical trials that highlight the potential of these approaches to effect dramatic and potent anti-tumor immunity.
TCR-Engineered Lymphocytes Targeting NY-ESO-1: In Vitro Assessment of Cytotoxicity against Tumors. [2023]Adoptive T-cell therapies tailored for the treatment of solid tumors encounter intricate challenges, necessitating the meticulous selection of specific target antigens and the engineering of highly specific T-cell receptors (TCRs). This study delves into the cytotoxicity and functional characteristics of in vitro-cultured T-lymphocytes, equipped with a TCR designed to precisely target the cancer-testis antigen NY-ESO-1. Flow cytometry analysis unveiled a notable increase in the population of cells expressing activation markers upon encountering the NY-ESO-1-positive tumor cell line, SK-Mel-37. Employing the NanoString platform, immune transcriptome profiling revealed the upregulation of genes enriched in Gene Ontology Biological Processes associated with the IFN-γ signaling pathway, regulation of T-cell activation, and proliferation. Furthermore, the modified T cells exhibited robust cytotoxicity in an antigen-dependent manner, as confirmed by the LDH assay results. Multiplex immunoassays, including LEGENDplex™, additionally demonstrated the elevated production of cytotoxicity-associated cytokines driven by granzymes and soluble Fas ligand (sFasL). Our findings underscore the specific targeting potential of engineered TCR T cells against NY-ESO-1-positive tumors. Further comprehensive in vivo investigations are essential to thoroughly validate these results and effectively harness the intrinsic potential of genetically engineered T cells for combating cancer.
TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. [2023]Genetically engineered T cell therapy can induce remarkable tumor responses in hematologic malignancies. However, it is not known if this type of therapy can be applied effectively to epithelial cancers, which account for 80-90% of human malignancies. We have conducted a first-in-human, phase 1 clinical trial of T cells engineered with a T cell receptor targeting HPV-16 E7 for the treatment of metastatic human papilloma virus-associated epithelial cancers (NCT02858310). The primary endpoint was maximum tolerated dose. Cell dose was not limited by toxicity with a maximum dose of 1 × 1011 engineered T cells administered. Tumor responses following treatment were evaluated using RECIST (Response Evaluation Criteria in Solid Tumors) guidelines. Robust tumor regression was observed with objective clinical responses in 6 of 12 patients, including 4 of 8 patients with anti-PD-1 refractory disease. Responses included extensive regression of bulky tumors and complete regression of most tumors in some patients. Genomic studies, which included intra-patient tumors with dichotomous treatment responses, revealed resistance mechanisms from defects in critical components of the antigen presentation and interferon response pathways. These findings demonstrate that engineered T cells can mediate regression of common carcinomas, and they reveal immune editing as a constraint on the curative potential of cellular therapy and possibly other immunotherapies in advanced epithelial cancer.
T cell receptor-engineered T cells to treat solid tumors: T cell processing toward optimal T cell fitness. [2018]Therapy with autologous T cells that have been gene-engineered to express chimeric antigen receptors (CAR) or T cell receptors (TCR) provides a feasible and broadly applicable treatment for cancer patients. In a clinical study in advanced renal cell carcinoma (RCC) patients with CAR T cells specific for carbonic anhydrase IX (CAIX), we observed toxicities that (most likely) indicated in vivo function of CAR T cells as well as low T cell persistence and clinical response rates. The latter observations were confirmed by later clinical trials in other solid tumor types and other gene-modified T cells. To improve the efficacy of T cell therapy, we have redefined in vitro conditions to generate T cells with young phenotype, a key correlate with clinical outcome. For their impact on gene-modified T cell phenotype and function, we have tested various anti-CD3/CD28 mAb-based T cell activation and expansion conditions as well as several cytokines prior to and/or after gene transfer using two different receptors: CAIX CAR and MAGE-C2(ALK)/HLA-A2 TCR. In a total set of 16 healthy donors, we observed that T cell activation with soluble anti-CD3/CD28 mAbs in the presence of both IL15 and IL21 prior to TCR gene transfer resulted in enhanced proportions of gene-modified T cells with a preferred in vitro phenotype and better function. T cells generated according to these processing methods demonstrated enhanced binding of pMHC, and an enhanced proportion of CD8+, CD27+, CD62L+, CD45RA+T cells. These new conditions will be translated into a GMP protocol in preparation of a clinical adoptive therapy trial to treat patients with MAGE-C2-positive tumors.
Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting. [2023]Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumor microenvironments. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies, which are being harnessed to improve solid tumor CAR T cell therapies. Here, we describe fully optimized CAR T cells targeting tumor-associated glycoprotein-72 (TAG72) for the treatment of solid tumors, identifying the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. These findings have culminated into a phase 1 trial evaluating safety, feasibility, and bioactivity of TAG72-CAR T cells for the treatment of patients with advanced ovarian cancer ( NCT05225363 ). Preclinically, we found that CAR T cell-mediated IFNγ production facilitated by IL-12 signaling was required for tumor cell killing, which was recapitulated by expressing an optimized membrane-bound IL-12 (mbIL12) molecule on CAR T cells. Critically, mbIL12 cell surface expression and downstream signaling was induced and sustained only following CAR T cell activation. CAR T cells with mbIL12 demonstrated improved antigen-dependent T cell proliferation and potent cytotoxicity in recursive tumor cell killing assays in vitro and showed robust in vivo anti-tumor efficacy in human xenograft models of ovarian cancer peritoneal metastasis. Further, locoregional administration of TAG72-CAR T cells with antigen-dependent IL-12 signaling promoted durable anti-tumor responses against both regional and systemic disease in mice and was associated with improved systemic T cell persistence. Our study features a clinically-applicable strategy to improve the overall efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting both regional and systemic disease.
Improving the efficacy and safety of engineered T cell therapy for cancer. [2020]Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is a powerful immunotherapeutics approach against metastatic melanoma. The success of TIL therapy has led to novel strategies for redirecting normal T cells to recognize tumor-associated antigens (TAAs) by genetically engineering tumor antigen-specific T cell receptors (TCRs) or chimeric antigen receptor (CAR) genes. In this manner, large numbers of antigen-specific T cells can be rapidly generated compared with the longer term expansion of TILs. Great efforts have been made to improve these approaches. Initial clinical studies have demonstrated that genetically engineered T cells can mediate tumor regression in vivo. In this review, we discuss the development of TCR and CAR gene-engineered T cells and the safety concerns surrounding the use of these T cells in patients. We highlight the importance of judicious selection of TAAs for modified T cell therapy and propose solutions for potential "on-target, off-organ" toxicity.
Development of adoptive cell therapy for cancer: a clinical perspective. [2021]Adoptive cellular therapy provides the promise of a potentially powerful general treatment for cancer. Although this is a complex and challenging field, there have been major advances in basic and translational research resulting in clinical trial activity that is now beginning to confirm this promise. However, these trials are also identifying new challenges and this review focuses on these clinical issues. For tumors such as melanoma, in which tumor-specific T cells can be readily identified and isolated, the adoptive transfer of "tumor-infiltrating lymphocytes" (TILs) already appears to offer significant patient benefit and this approach now warrants further development. Genetically engineered T cells offer a means to endow peripheral blood T cells with antitumor activity and in principle these techniques could allow the treatment of a wide range of cancers. Genetic engineering also offers the means to endow T cells with new properties and enhanced functions. There have been clear proof-of-principle trials showing responses with T cell receptor (TCR)-engineered T cells and this can be built on with further development. By contrast, other trials have produced significant toxicity related to expression of target antigen on normal tissue, particularly with enhanced receptors. The challenge ahead lies in understanding how to achieve the balance between targeted antitumor immune responses while avoiding toxicity associated with on-target destruction of antigen-expressing normal tissues. Cellular therapy of cancer will need continued preclinical evaluation as well as carefully designed clinical trials addressing the various issues. For these challenges to be fully assessed, and for progression to a widely used, effective and safe therapy, development as cooperative groups is an appropriate way forward.
Patient-reported outcome (PRO) instruments used in patients undergoing adoptive cell therapy (ACT) for the treatment of cancer: a systematic review. [2023]Adoptive cell therapy (ACT) is a rapidly evolving field. Patient-reported outcomes (PROs) allow patients to report the impact of treatment on their quality of life during and after treatment. The systematic review aims to characterise the breadth of PROs utilised in ACT cancer care and provide guidance for the use of PROs in this patient population in the future.
Nonclinical safety assessment of engineered T cell therapies. [2022]Over the last decade, immunotherapy has established itself as an important novel approach in the treatment of cancer, resulting in a growing importance in oncology. Engineered T cell therapies, namely chimeric antigen receptor (CAR) T cells and T cell receptor (TCR) T cell therapies, are platform technologies that have enabled the development of products with remarkable efficacy in several hematological malignancies and are thus the focus of intense research and development activity. While engineered T cell therapies offer promise in addressing currently intractable cancers, they also present unique challenges, including their nonclinical safety assessment. A workshop organized by HESI and the US Food and Drug Administration (FDA) was held to provide an interdisciplinary forum for representatives of industry, academia and regulatory authorities to share information and debate on current practices for the nonclinical safety evaluation of engineered T cell therapies. This manuscript leverages what was discussed at this workshop to provide an overview of the current important nonclinical safety assessment considerations for the development of these therapeutic modalities (cytokine release syndrome, neurotoxicity, on-target/off-tumor toxicities, off-target effects, gene editing or vector integration-associated genomic injury). The manuscript also discusses approaches used for hazard identification or risk assessment and provides a regulatory perspective on such aspects.
Engineered T cells for anti-cancer therapy. [2021]Recent advances enabling efficient delivery of transgenes to human T cells have created opportunities to address obstacles that previously hindered the application of T cell therapy to cancer. Modification of T cells with transgenes encoding TCRs or chimeric antigen receptors allows tumor specificity to be conferred on functionally distinct T cell subsets, and incorporation of costimulatory molecules or cytokines can enable engineered T cells to bypass local and systemic tolerance mechanisms. Clinical studies of genetically modified T cell therapy for cancer have shown notable success; however, these trials demonstrate that tumor therapy with engineered high avidity tumor-reactive T cells may be accompanied by significant on-target toxicity, necessitating careful selection of target antigens and development of strategies to eliminate transferred cells.
T Cells as the Future of Cancer Therapy. [2022]In the next 10 years, gene-engineered T-cell therapies have the potential to provide broad benefit for the treatment of patients with cancer. Advances in immunology, molecular biology, and bioengineering allow the design of gene-engineered T cells that actively target metastatic lesions, specifically recognize and kill cancer cells, and maintain long-term immunologic memory.
Engineered T cells for cancer treatment. [2021]Adoptively transferred T cells have the capacity to traffic to distant tumor sites, infiltrate fibrotic tissue and kill antigen-expressing tumor cells. Various groups have investigated different genetic engineering strategies designed to enhance tumor specificity, increase T cell potency, improve proliferation, persistence or migratory capacity and increase safety. This review focuses on recent developments in T cell engineering, discusses the clinical application of these engineered cell products and outlines future prospects for this therapeutic modality.
The next step toward GMP-grade production of engineered immune cells. [2021]Removing less potent T cell subsets as well as poorly- or non-engineered cells can optimize effectiveness of engineered T cell therapy against cancer. We have recently described a novel, GMP-ready method for the purification of engineered immune cells that might further boost the clinical success of cancer immunotherapy.