Cellular Therapy for Brain Tumors
(ADAGiO Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University of Florida
Must not be taking: Corticosteroids, Immunosuppressants, others
Disqualifiers: HIV, Hepatitis B, Hepatitis C, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This study will enroll 6 DLT evaluable subjects (up to 12 patients total) where we will evaluate feasibility and safety of adoptive cellular therapy combined with IDH1/2 inhibitors in patients with recurrent or progressive oligodendroglioma WHO grade 2 and WHO grade 3.
Will I have to stop taking my current medications?
The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are on corticosteroids equivalent to 4mg or more of dexamethasone daily or if you have taken another investigational drug within 30 days before the study treatment.
What data supports the effectiveness of the treatment Cellular Therapy for Brain Tumors?
Research shows that using dendritic cells (a type of immune cell) pulsed with tumor RNA can stimulate the body's immune response against tumors. In a study with children having brain tumors, this approach was safe and led to stable disease in some patients. Additionally, using mRNA-transfected dendritic cells has shown promise in generating strong immune responses in cancer patients, suggesting potential effectiveness for brain tumors.
12345Is cellular therapy for brain tumors generally safe in humans?
Research shows that dendritic cell-based vaccines, including those using tumor RNA, have been proven safe in clinical trials for various cancers, including brain tumors, with no significant short or long-term side effects reported.
12356How is the TTRNA-DC vaccine treatment for brain tumors different from other treatments?
The TTRNA-DC vaccine treatment is unique because it uses a patient's own dendritic cells (a type of immune cell) that are 'pulsed' with RNA from the patient's tumor to create a personalized vaccine. This approach aims to stimulate the immune system to specifically target and attack the tumor, which is different from traditional treatments that may not be as targeted.
12378Eligibility Criteria
This trial is for adults with a type of brain tumor called oligodendroglioma that has come back or gotten worse. They must be able to undergo certain medical procedures and treatments.Inclusion Criteria
Adequate bone marrow and organ function: ANC ≥ 1,000/mcL, Platelets ≥ 100,000/mcL, Hemoglobin ≥ 9 g/dL (can be transfused), Serum creatinine ≤ 1.5 x IULN OR Creatinine clearance by Cockcroft-Gault ≥ 60 mL/min for patients with serum creatinine > 1.5 x IULN, Serum total bilirubin ≤ 1.5 x IULN OR Direct bilirubin ≤ IULN for patients with total bilirubin > 1.5 x IULN, AST (SGOT) and ALT (SGPT) ≤ 3 x IULN, Negative serum pregnancy test at enrollment for females of childbearing potential, Willingness to use acceptable contraceptive methods for women and men of childbearing potential
I am eligible for surgery or a biopsy.
I am 18 years old or older.
+3 more
Exclusion Criteria
I am taking a steroid dose equal to or more than 4mg of dexamethasone daily.
My cancer is present in multiple locations.
Pregnancy or lactation
+8 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Surgery and Biopsy
Subjects undergo standard of care resection or biopsy for confirmatory diagnosis and collection of tumor material for DNA and RNA extraction
1-2 weeks
1 visit (in-person)
Chemotherapy and Vaccine Priming
Patients initiate salvage chemotherapy with IDH1/2 inhibitor and receive 3 priming TTRNA-DCs vaccines every 2 weeks
6-8 weeks
3 visits (in-person)
T Cell Expansion and Vaccination
Patients undergo non-mobilized leukapheresis for T cell expansion and receive monthly TTRNA-DC vaccines for 2-3 cycles
2-3 months
2-3 visits (in-person)
Adoptive Cellular Therapy
Patients receive a single i.v. infusion of ex vivo expanded tumor-reactive T cells and autologous HSCs
1 day
1 visit (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment, including assessment of dose-limiting toxicity
6 weeks
2 visits (in-person)
Participant Groups
The study tests adoptive cellular therapy, which includes TTRNA-DC vaccines with GM-CSF, autologous hematopoietic stem cells (HSCs), TTRNA-xALT, and the Td vaccine to see if they are safe and workable for these patients.
1Treatment groups
Experimental Treatment
Group I: Adoptive Cellular TherapyExperimental Treatment4 Interventions
All participants will receive 9 intradermal DC vaccines (three -bi-weekly (q2 weeks) for priming, monthly for additional 2-3 cycles during T cell expansion, and three bi-weekly during T cell engraftment), a single i.v. infusion of ex vivo expanded tumor-reactive T cells, and a i.v. single infusion of autologous HSCs.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Florida Health Shands HospitalGainesville, FL
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Who Is Running the Clinical Trial?
University of FloridaLead Sponsor
Oligo Nation, IncCollaborator
References
A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model. [2021]Adoptive cell transfer (ACT) using ex vivo-expanded anti-tumor T cells such as tumor-infiltrated lymphocytes or genetically engineered T cells potently eradicates established tumors. However, these two approaches possess obvious limitations. Therefore, we established a novel methodology using total tumor RNA (ttRNA) to prime dendritic cells (DC) as a platform for the ex vivo generation of anti-tumor T cells. We evaluated the antigen-specific expansion and recognition of T cells generated by the ttRNA-DC-T platform, and directly modulated the differentiation status of these ex vivo-expanded T cells with a cytokine cocktail. Furthermore, we evaluated the persistence and in vivo anti-tumor efficacy of these T cells through murine xenograft and syngeneic tumor models. During ex vivo culture, IL-2 preferentially expanded CD4 subset, while IL-7 enabled homeostatic proliferation from the original precursors. T cells tended to lose CD62L during ex vivo culture using IL-2; however, IL-12 could maintain high levels of CD62L by increasing expression on effector T cells (Tem). In addition, we validated that OVA RNA-DC only selectively expanded T cells in an antigen-specific manner. A cytokine cocktail excluding the use of IL-2 greatly increased CD62Lhigh T cells which specifically recognized tumor cells, engrafted better in a xenograft model and exhibited superior anti-tumor activities in a syngeneic intracranial model. ACT using the ex vivo ttRNA-DC-T platform in conjunction with a cytokine cocktail generated potent CD62Lhigh anti-tumor T cells and imposes a novel T cell-based therapeutic with the potential to treat brain tumors and other cancers.
Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer. [2020]We conducted a phase 1 study of 9 pediatric patients with recurrent brain tumors using monocyte-derived dendritic cells pulsed with tumor RNA to produce antitumor vaccine (DCRNA) preparations. The objectives of this study included (1) establishing safety and feasibility and (2) measuring changes in general, antigen-specific, and tumor-specific immune responses after DCRNA. Dendritic cells were derived from freshly isolated monocytes after 7 days of culture with IL-4 and granulocyte-macrophage colony-stimulating factor, pulsed with autologous tumor RNA, and then cryopreserved. Patients received at least 3 vaccines, each consisting of an intravenous and an intradermal administration at biweekly intervals. The study showed that this method for producing and administering DCRNA from a single leukapheresis product was both feasible and safe in this pediatric brain tumor population. Immune function at the time of enrollment into the study was impaired in all patients tested. While humoral responses to recall antigens (diphtheria and tetanus) were intact in all patients, cellular responses to mitogen and recall antigens were below normal. Following DCRNA vaccine, 2 of 7 patients showed stable clinical disease and 1 of 7 showed a partial response. Two of 7 patients who were tested showed a tumor-specific immune response to DCRNA. This study showed that DCRNA vaccines are both safe and feasible in children with tumors of the central nervous system with a single leukapheresis.
Tumor vaccine therapy against recrudescent tumor using dendritic cells simultaneously transfected with tumor RNA and granulocyte macrophage colony-stimulating factor RNA. [2017]Recently, dendritic cells (DC) transfected with tumor RNA have been used as a cancer vaccine. The efficacy of a cancer vaccine using DC transfected tumor RNA was examined. Of particular interest was whether a vaccine using DC transfected with recrudescent tumor RNA is effective for the treatment of a regrowing tumor after prior immunotherapy. In addition, the usefulness of co-transfection of granulocyte macrophage colony-stimulating factor (GM-CSF) mRNA to augment the DC vaccine was examined. CT26 tumor-bearing mice were immunized by s.c. injection with DC transfected with CT26 mRNA (DC-CT26). The cytotoxic activity against CT26 in mice immunized with DC-CT26 was significantly higher than that in the control group (P
Cancer immunotherapy with mRNA-transfected dendritic cells. [2022]Bone marrow-derived dendritic cells (DCs) are the most potent antigen-presenting cells capable of activating naïve T cells. Loading DCs ex vivo with tumor antigens can stimulate potent antitumor immunity in tumor-bearing mice. This review describes the use of mRNA-encoded tumor antigens as a form of antigen loaded onto DCs, including our early experience from clinical trials in urological cancers. Transfection of DCs with mRNA is simple and effective. Comparative studies suggest that mRNA transfection is superior to other antigen-loading techniques in generating immunopotent DCs. The ability to amplify RNA from microscopic amounts of tumor tissue extends the use of DC vaccination to virtually every cancer patient. The striking observation from two phase I clinical trials, in patients with prostate cancer immunized with prostate-specific antigen mRNA-transfected DCs and patients with renal cancer immunized with autologous tumor RNA-transfected DCs, was that the majority of patients exhibited a vaccine-induced T-cell response. Suggestive evidence of clinically related responses was seen in both the trials. Immunization with mRNA-transfected DCs is a promising strategy to stimulate potent antitumor immunity and could serve as a foundation for developing effective treatments for cancer.
Delivery of Synthetic mRNA Encoding FOXP3 Antigen into Dendritic Cells for Inflammatory Breast Cancer Immunotherapy. [2018]Dendritic cell (DC)-based vaccines are commonly used for cancer immunotherapy. To prepare vaccines, DCs are pulsed or transfected with either: (a) defined peptides of tumor-associated antigens, (b) total protein isolated from the tumor cell, (c) autologous total RNA isolated from the tumor cell, (d) synthetic tumor-antigen-encoding mRNA, or (e) genes that encode for specific tumor-associated antigens. Introduction of tumor-associated antigen(s) and subsequent generation of mature DCs that can stimulate tumor-antigen-specific cytotoxic T lymphocytes comprise the critical steps of cancer vaccine preparation. Here, we described a method of: (a) preparing and delivering synthetic FOXP3 mRNA into human DCs, (b) generating mature DCs,
Therapeutic Cancer Vaccination with Ex Vivo RNA-Transfected Dendritic Cells-An Update. [2020]Over the last two decades, dendritic cell (DC) vaccination has been studied extensively as active immunotherapy in cancer treatment and has been proven safe in all clinical trials both with respect to short and long-term side effects. For antigen-loading of dendritic cells (DCs) one method is to introduce mRNA coding for the desired antigens. To target the whole antigenic repertoire of a tumor, even the total tumor mRNA of a macrodissected biopsy sample can be used. To date, reports have been published on a total of 781 patients suffering from different tumor entities and HIV-infection, who have been treated with DCs loaded with mRNA. The majority of those were melanoma patients, followed by HIV-infected patients, but leukemias, brain tumors, prostate cancer, renal cell carcinomas, pancreatic cancers and several others have also been treated. Next to antigen-loading, mRNA-electroporation allows a purposeful manipulation of the DCs' phenotype and function to enhance their immunogenicity. In this review, we intend to give a comprehensive summary of what has been published regarding clinical testing of ex vivo generated mRNA-transfected DCs, with respect to safety and risk/benefit evaluations, choice of tumor antigens and RNA-source, and the design of better DCs for vaccination by transfection of mRNA-encoded functional proteins.
Generation of Ag-specific cytotoxic T lymphocytes by DC transfected with in vitro transcribed influenza virus matrix protein (M1) mRNA. [2015]Application of DC transfected with tumor Ag RNA is promising for DC-based tumor immunotherapy. In this study, Ag-specific cytotoxic T lymphocytes (CTL) were generated by priming lymphocytes with DC transfected with in vitro transcribed (IVT) influenza virus matrix protein M1 (M1) mRNA.
[Dendritic cells pulsed with glioma RNA induce immunity against intracranial gliomas]. [2022]To investigate the anti-tumor effect of dendritic cells (DC) pulsed with G422 glioblastomas RNA in mice bearing intracranially G422 glioblastomas.