Gene Transfer Therapy for Metastatic Cancer
Recruiting in Palo Alto (17 mi)
Overseen bySteven A Rosenberg, M.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: Systemic steroids
Disqualifiers: Pregnancy, Active infections, Autoimmune disease, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?Background:
A person s tumor is studied for mutations. When cells are found that can attack the mutation in a person s tumor, the genes from those cells are studied to find the parts that make the attack possible. White blood cells are then taken from the person s body, and the gene transfer occurs in a laboratory. A type of virus is used to transfer the genes that make those white blood cells able to attack the mutation in the tumor. The gene transfer therapy is the return of those white blood cells back to the person.
Objective:
To see if gene transfer therapy of white blood cells can shrink tumors.
Eligibility:
People with certain metastatic cancer for which standard treatments have not worked.
Design:
Participants may complete screening under another protocol. Screening includes:
* Getting tumor cells from a previous procedure
* Medical history
* Physical exam
* Scans
* Blood, urine, heart, and lung tests
The study has 8 stages:
1. Screening tests repeated over 1-2 weeks. Participants will have leukapheresis: Blood is removed by a needle in one arm. A machine removes white blood cells. The rest of the blood is returned by a needle in the other arm.
2. Care at home over approximately 12 weeks.
3. Stopping therapy for 4-6 weeks while their cells are changed in a lab.
4. Hospital stay approximately 3-4 weeks for treatment. An IV catheter will be placed in the chest to administer drugs.
5. Patients on Arm 2 of the study will receive the first dose of pembrolizumab while in the hospital. Three additional doses will be given after the cell infusion 3 weeks apart.
6. Receiving changed cells by catheter. Then getting a drug over 1-5 days to help the cells live longer.
7. Recover in the hospital for 1-2 weeks. Participants will get drugs and have blood and urine tests.
8. Participants will take an antibiotic and maybe an antiviral for at least 6 months after treatment. They will have repeat screening tests at visits every few months for the first year, every 6 months for the second year, then as determined.
Will I have to stop taking my current medications?
The trial protocol does not specify if you must stop taking your current medications. However, participants must have completed any prior systemic therapy before enrollment, and concurrent systemic steroid therapy is not allowed.
What data supports the effectiveness of this treatment for metastatic cancer?
Research shows that T-cell receptor (TCR) gene therapy, which involves modifying T-cells to target cancer cells, has demonstrated promising antitumor effects in humans. Studies have shown that TCR-engineered T cells can mediate tumor regression and are functionally competent, suggesting potential effectiveness for treating metastatic cancer.
12345Is gene transfer therapy for metastatic cancer generally safe in humans?
The research articles do not provide specific safety data for gene transfer therapy in humans, but they discuss the potential of T-cell receptor (TCR) therapies to target cancer cells. While these studies focus on the effectiveness and development of the therapy, they do not directly address safety outcomes.
12678How is the treatment Individual Patient TCR-Transduced PBL different from other treatments for metastatic cancer?
This treatment is unique because it involves genetically engineering a patient's own T-cells to specifically target cancer cells, which can lead to a more precise attack on the tumor compared to traditional therapies. It uses T-cell receptors (TCRs) to recognize and attack cancer cells, potentially offering a more personalized and effective approach for patients with metastatic cancer.
3491011Eligibility Criteria
This trial is for adults aged 18-72 with certain metastatic cancers that haven't responded to standard treatments. Participants must be in good physical condition, not have HIV or hepatitis, agree to use birth control, and sign consent forms. Pregnant women and those with major illnesses or hypersensitivity reactions are excluded.Inclusion Criteria
Willingness to practice birth control and undergo pregnancy testing
You need to have certain levels of blood and chemical components in your body.
I am between 18 and 72 years old.
+9 more
Exclusion Criteria
Receiving any other investigational agents
I am currently pregnant or breastfeeding.
I am currently taking steroid medication.
+6 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
1-2 weeks
Multiple visits for tests and leukapheresis
Care at Home
Participants care for themselves at home while their cells are modified in the lab
12 weeks
Treatment
Participants receive a non-myeloablative, lymphodepleting preparative regimen followed by infusion of modified cells and high-dose aldesleukin
3-4 weeks
Hospital stay for treatment
Pembrolizumab Administration
Participants on Arm 2 receive pembrolizumab prior to cell administration and three additional doses every three weeks following the cell infusion
9 weeks
Recovery
Participants recover in the hospital, receiving drugs and undergoing blood and urine tests
1-2 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment, with repeat screening tests at visits every few months for the first year, every 6 months for the second year, then as determined
2 years
Regular visits every few months
Participant Groups
The study tests gene transfer therapy using the patient's own white blood cells engineered to attack cancer mutations. It involves leukapheresis, cell modification in a lab, hospital treatment including drug administration via catheter, recovery period with medications and follow-up visits.
2Treatment groups
Experimental Treatment
Group I: 2/iTCR + PembroExperimental Treatment5 Interventions
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Individual Patient TCRTransduced PBL + high- or low-dose aldesleukin + pembrolizumab prior to cell administration and 3 additional doses every 3 weeksfollowing cell infusion
Group II: 1/iTCRExperimental Treatment4 Interventions
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Individual Patient TCR-Transduced PBL + high- or low-dose aldesleukin
Individual Patient TCR-Transduced PBL is already approved in United States for the following indications:
🇺🇸 Approved in United States as Afami-cel (Tecelra) for:
- Metastatic synovial sarcoma positive for MAGE-A4 and certain HLA proteins
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
Multifunctional T-cell analyses to study response and progression in adoptive cell transfer immunotherapy. [2022]Adoptive cell transfer (ACT) of genetically engineered T cells expressing cancer-specific T-cell receptors (TCR) is a promising cancer treatment. Here, we investigate the in vivo functional activity and dynamics of the transferred cells by analyzing samples from 3 representative patients with melanoma enrolled in a clinical trial of ACT with TCR transgenic T cells targeted against the melanosomal antigen MART-1. The analyses included evaluating 19 secreted proteins from individual cells from phenotypically defined T-cell subpopulations, as well as the enumeration of T cells with TCR antigen specificity for 36 melanoma antigens. These analyses revealed the coordinated functional dynamics of the adoptively transferred, as well as endogenous, T cells, and the importance of highly functional T cells in dominating the antitumor immune response. This study highlights the need to develop approaches to maintaining antitumor T-cell functionality with the aim of increasing the long-term efficacy of TCR-engineered ACT immunotherapy.
The Promise of Personalized TCR-Based Cellular Immunotherapy for Cancer Patients. [2021]Mutation-derived neoantigens are now established as attractive targets for cancer immunotherapy. The field of adoptive T cell transfer (ACT) therapy was significantly reshaped by tumor neoantigens and is now moving towards the genetic engineering of T cells with neoantigen-specific T cell receptors (TCRs). Yet, the identification of neoantigen-reactive TCRs remains challenging and the process needs to be adapted to clinical timelines. In addition, the state of recipient T cells for TCR transduction is critical and can affect TCR-ACT efficacy. Here we provide an overview of the main strategies for TCR-engineering, describe the selection and expansion of optimal carrier cells for TCR-ACT and discuss the next-generation methods for rapid identification of relevant TCR candidates for gene transfer therapy.
Genetic engineering with T cell receptors. [2023]In the past two decades, human gene transfer research has been translated from a laboratory technology to clinical evaluation. The success of adoptive transfer of tumor-reactive lymphocytes to treat the patients with metastatic melanoma has led to new strategies to redirect normal T cells to recognize tumor antigens by genetic engineering with tumor antigen-specific T cell receptor (TCR) genes. This new strategy can generate large numbers of defined antigen-specific cells for therapeutic application. Much progress has been made to TCR gene transfer systems by optimizing gene expression and gene transfer protocols. Vector and protein modifications have enabled excellent expression of introduced TCR chains in human lymphocytes with reduced mis-pairing between the introduced and endogenous TCR chains. Initial clinical studies have demonstrated that TCR gene-engineered T cells could mediate tumor regression in vivo. In this review, we discuss the progress and prospects of TCR gene-engineered T cells as a therapeutic strategy for treating patients with melanoma and other cancers.
Exploiting T cell receptor genes for cancer immunotherapy. [2018]Adoptive antigen-specific immunotherapy is an attractive concept for the treatment of cancer because it does not require immunocompetence of patients, and the specificity of transferred lymphocytes can be targeted against tumour-associated antigens that are poorly immunogenic and thus fail to effectively trigger autologous T cell responses. As the isolation and in vitro expansion of antigen-specific lymphocytes is difficult, 'conventional' adoptive T cell therapy can only be carried out in specialized centres in small numbers of patients. However, T cell receptor (TCR) genes isolated from antigen-specific T cells can be exploited as generic therapeutic molecules for 'unconventional' antigen-specific immunotherapy. Retroviral TCR gene transfer into patient T cells can readily produce populations of antigen-specific lymphocytes after a single round of polyclonal T cell stimulation. TCR gene modified lymphocytes are functionally competent in vitro, and can have therapeutic efficacy in murine models in vivo. TCR gene expression is stable and modified lymphocytes can develop into memory T cells. Introduction of TCR genes into CD8(+) and CD4(+) lymphocytes provides an opportunity to use the same TCR specificity to produce antigen-specific killer and helper T lymphocytes. Thus, TCR gene therapy provides an attractive strategy to develop antigen-specific immunotherapy with autologous lymphocytes as a generic treatment option.
T-cell receptor gene therapy for cancer: the progress to date and future objectives. [2019]In the last decade research has begun into the use of T-cell receptor (TCR) gene therapy as a means to control and eradicate malignancies. There is now a large body of evidence to demonstrate that through the use of this technology one can redirect T-cell antigen specificity to produce both cytotoxic and helper T cells, which are functionally competent both in vitro and in vivo and show promising antitumour effects in humans. This review focuses on the means by which TCR gene transfer is achieved and the recent advances to modify the TCRs and vector delivery systems which aim to enhance the efficiency and safety of TCR gene transfer protocols.
Tumor- and Neoantigen-Reactive T-cell Receptors Can Be Identified Based on Their Frequency in Fresh Tumor. [2021]Adoptive transfer of T cells with engineered T-cell receptor (TCR) genes that target tumor-specific antigens can mediate cancer regression. Accumulating evidence suggests that the clinical success of many immunotherapies is mediated by T cells targeting mutated neoantigens unique to the patient. We hypothesized that the most frequent TCR clonotypes infiltrating the tumor were reactive against tumor antigens. To test this hypothesis, we developed a multistep strategy that involved TCRB deep sequencing of the CD8(+)PD-1(+) T-cell subset, matching of TCRA-TCRB pairs by pairSEQ and single-cell RT-PCR, followed by testing of the TCRs for tumor-antigen specificity. Analysis of 12 fresh metastatic melanomas revealed that in 11 samples, up to 5 tumor-reactive TCRs were present in the 5 most frequently occurring clonotypes, which included reactivity against neoantigens. These data show the feasibility of developing a rapid, personalized TCR-gene therapy approach that targets the unique set of antigens presented by the autologous tumor without the need to identify their immunologic reactivity. Cancer Immunol Res; 4(9); 734-43. ©2016 AACR.
Stable, Nonviral Expression of Mutated Tumor Neoantigen-specific T-cell Receptors Using the Sleeping Beauty Transposon/Transposase System. [2018]Neoantigens unique to each patient's tumor can be recognized by autologous T cells through their T-cell receptor (TCR) but the low frequency and/or terminal differentiation of mutation-specific T cells in tumors can limit their utility as adoptive T-cell therapies. Transfer of TCR genes into younger T cells from peripheral blood with a high proliferative potential could obviate this problem. We generated a rapid, cost-effective strategy to genetically engineer cancer patient T cells with TCRs using the clinical Sleeping Beauty transposon/transposase system. Patient-specific TCRs reactive against HLA-A*0201-restriced neoantigens AHNAK(S2580F) or ERBB2(H473Y) or the HLA-DQB*0601-restricted neoantigen ERBB2IP(E805G) were assembled with murine constant chains and cloned into Sleeping Beauty transposons. Patient peripheral blood lymphocytes were coelectroporated with SB11 transposase and Sleeping Beauty transposon, and transposed T cells were enriched by sorting on murine TCRβ (mTCRβ) expression. Rapid expansion of mTCRβ(+) T cells with irradiated allogeneic peripheral blood lymphocytes feeders, OKT3, interleukin-2 (IL-2), IL-15, and IL-21 resulted in a preponderance of effector (CD27(-)CD45RA(-)) and less-differentiated (CD27(+)CD45RA(+)) T cells. Transposed T cells specifically mounted a polyfunctional response against cognate mutated neoantigens and tumor cell lines. Thus, Sleeping Beauty transposition of mutation-specific TCRs can facilitate the use of personalized T-cell therapy targeting unique neoantigens.
Assessing TCR identity, knock-in efficiency, and potency for individualized TCR-T cell therapy. [2023]Advances in mass spectrometry, genome sequencing techniques, and bioinformatic strategies have accelerated the discovery of cancer-specific neoantigens. Tumors express multiple immunogenic neoantigens, and neoantigen-specific T cell receptors (TCRs) can be identified in peripheral blood's mononuclear cells in cancer patients. Therefore, individualized TCR-based therapies are a promising approach whereby multiple neoantigen-specific TCRs can be selected in each patient, potentially leading to a highly effective treatment for cancer patients. We developed three multiplex analytical assays to determine the quality attributes of the TCR-T cell drug product with a mixture of five engineered TCRs. The identity of each TCR was determined by two NGS-based methods, Illumina MiSeq and PacBio platforms. This approach not only confirms the expected TCR sequences but also differentiates them by their variable regions. The five individual TCR and total TCR knock-in efficiencies were measured by droplet digital PCR using specific reverse primers. A potency assay based on transfection of antigen-encoding-RNA was developed to assess the dose-dependent activation of T cells for each TCR by measuring the surface activation marker CD137 expression and cytokine secretion. This work provides new assays to characterize individualized TCR-T cell products and insights into quality attributes for the control strategy.
Cancer regression in patients after transfer of genetically engineered lymphocytes. [2023]Through the adoptive transfer of lymphocytes after host immunodepletion, it is possible to mediate objective cancer regression in human patients with metastatic melanoma. However, the generation of tumor-specific T cells in this mode of immunotherapy is often limiting. Here we report the ability to specifically confer tumor recognition by autologous lymphocytes from peripheral blood by using a retrovirus that encodes a T cell receptor. Adoptive transfer of these transduced cells in 15 patients resulted in durable engraftment at levels exceeding 10% of peripheral blood lymphocytes for at least 2 months after the infusion. We observed high sustained levels of circulating, engineered cells at 1 year after infusion in two patients who both demonstrated objective regression of metastatic melanoma lesions. This study suggests the therapeutic potential of genetically engineered cells for the biologic therapy of cancer.
TCR-engineered T cells to treat tumors: Seeing but not touching? [2021]Adoptive transfer of T cells gene-engineered with T cell receptors (TCRs) has proven its feasibility and therapeutic potential in the treatment of malignant tumors. To ensure further clinical development of TCR gene therapy, it is necessary to accurately select TCRs that demonstrate antigen-selective responses that are restricted to tumor cells and, at the same time, include strategies that restore or enhance the entry, migration and local accumulation of T cells in tumor tissues. Here, we present the current standing of TCR-engineered T cell therapy, discuss and propose procedures to select TCRs as well as strategies to sensitize the tumor to T cell trafficking, and provide a rationale for combination therapies with TCR-engineered T cells.
Prospects and limitations of T cell receptor gene therapy. [2019]Adoptive transfer of antigen-specific T cells is an attractive means to provide cancer patients with immune cells of a desired specificity and the efficacy of such adoptive transfers has been demonstrated in several clinical trials. Because the T cell receptor is the single specificity-determining molecule in T cell function, adoptive transfer of TCR genes into patient T cells may be used as an alternative approach for the transfer of tumor-specific T cell immunity. On theoretical grounds, TCR gene therapy has two substantial advantages over conventional cellular transfer. First, it circumvents the demanding process of in vitro generation of large numbers of specific immune cells. Second, it allows the use of a set of particularly effective TCR genes in large patient groups. Conversely, TCR gene therapy may be associated with a number of specific problems that are not confronted during classical cellular therapy. Here we review our current understanding of the potential and possible problems of TCR gene therapy, as based on in vitro experiments, mouse model systems and phase I clinical trials. Furthermore, we discuss the prospects of widespread clinical application of this gene therapy approach for the treatment of human cancer.