Adoptive Cellular Therapy for Brain Cancer
(PEACH Trial)
Recruiting in Palo Alto (17 mi)
+2 other locations
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Giselle SaulnierSholler
Must not be taking: Investigational drugs
Disqualifiers: Autoimmune, Immunosuppressive, Organ dysfunction, others
No Placebo Group
Trial Summary
What is the purpose of this trial?A Phase I open-label, multicenter study, to evaluate the safety, feasibility, and maximum tolerated dose (MTD) of treating children with newly diagnosed DIPG or recurrent neuroblastoma with molecular targeted therapy in combination with adoptive cell therapy (Total tumor mRNA-pulsed autologous Dendritic Cells (DCs) (TTRNA-DCs), Tumor-specific ex vivo expanded autologous lymphocyte transfer (TTRNA-xALT) and Autologous G-CSF mobilized Hematopoietic Stem Cells (HSCs)).
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, if you are taking steroids for CNS disease, you must be on a stable dose for at least one week before the biopsy.
What data supports the effectiveness of the treatment TTRNA-xALT for brain cancer?
Research shows that using tumor RNA-pulsed dendritic cells (DCs) can expand tumor-reactive T cells, which are effective in treating brain tumors in animal models. Additionally, these DCs have been shown to generate strong immune responses against tumors, suggesting potential effectiveness in treating brain cancer.
12345Is adoptive cellular therapy for brain cancer safe for humans?
Research shows that adoptive cellular therapy, including methods using dendritic cells pulsed with tumor RNA, has been generally safe in clinical trials for various cancers, including brain tumors. A phase 1 study in children with brain cancer found the treatment to be safe and feasible, with no major safety concerns reported.
12467How is the treatment TTRNA-xALT different from other treatments for brain cancer?
TTRNA-xALT is unique because it uses a patient's own immune cells, specifically dendritic cells and T cells, that are modified outside the body to recognize and attack brain cancer cells. This approach is different from traditional treatments as it involves a personalized immune response, potentially offering a more targeted and effective treatment for brain tumors.
13489Eligibility Criteria
This trial is for children with specific pediatric cancers like high-risk neuroblastoma or brain stem gliomas, who have no known effective curative therapy available. Participants must be aged ≤ 30 years, have a certain level of physical functioning (Lansky/Karnofsky Score ≥ 60), and agree to use effective birth control. They should not have significant organ dysfunction or other serious medical conditions that could affect the study.Inclusion Criteria
Informed Consent: All subjects and/or legal guardians must sign informed written consent
I am over 12 months old with neuroblastoma.
Women who could become pregnant need to have a negative pregnancy test.
+13 more
Exclusion Criteria
My biopsy did not show cancer or showed a type other than neuroblastoma or glioma.
Subjects with any other medical condition deemed by the Investigator to be likely to interfere with the interpretation of the results or which would interfere with a subject's ability to sign or the legal guardian's ability to sign the informed consent, and subject's ability to cooperate and participate in the study
Subjects receiving any investigational drug concurrently
+6 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive molecular targeted therapy in combination with adoptive cell therapy, including TTRNA-DCs, TTRNA-xALT, and autologous G-CSF mobilized HSCs
2 years
Follow-up
Participants are monitored for safety, effectiveness, and overall survival after treatment
7 years
Dose Escalation
A standard 3+3 dose escalation design to establish the maximum tolerated dose (MTD) with three pre-specified dose levels of xALT
Participant Groups
The PEACH TRIAL tests a combination of molecular targeted therapy with adoptive cell therapy in children with newly diagnosed DIPG or recurrent neuroblastoma. It aims to find the safest dose for treatments involving autologous dendritic cells, lymphocyte transfer, and hematopoietic stem cells.
2Treatment groups
Experimental Treatment
Group I: Arm 2: Relapsed/Refractory Neuroblastoma (NB)Experimental Treatment1 Intervention
This Phase I study is will utilize a standard 3+3 dose escalation design to establish the MTD and will evaluate the following three pre-specified dose levels of xALT:
Dose Level 1: 3 x10\^7 cells/kg Dose Level +1: 3 x10\^8 cells/kg Dose Level -1: 3 x10\^6 cells/kg
The dose escalation scheme will be evaluated for Arm 1 and Arm 2 separately. For each Study Arm, a minimum of 4 DLT evaluable subjects and a maximum of 12 DLT evaluable subjects will be enrolled (a total of 8 to 24 DLT evaluable subjects).
Group II: Arm 1: Subjects with Diffuse Intrinsic Pontine Glioma (DIPG).Experimental Treatment1 Intervention
This Phase I study is will utilize a standard 3+3 dose escalation design to establish the MTD and will evaluate the following three pre-specified dose levels of xALT:
Dose Level 1: 3 x10\^7 cells/kg Dose Level +1: 3 x10\^8 cells/kg Dose Level -1: 3 x10\^6 cells/kg
The dose escalation scheme will be evaluated for Arm 1 and Arm 2 separately. For each Study Arm, a minimum of 4 DLT evaluable subjects and a maximum of 12 DLT evaluable subjects will be enrolled (a total of 8 to 24 DLT evaluable subjects).
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of FloridaGainesville, FL
Levine Children's HospitalCharlotte, NC
Penn State Milton S. Hershey Medical Center and Children's HospitalHershey, PA
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Who Is Running the Clinical Trial?
Giselle SaulnierShollerLead Sponsor
Giselle ShollerLead Sponsor
University of FloridaLead Sponsor
Wake Forest University Health SciencesLead Sponsor
Beat Childhood Cancer Research ConsortiumCollaborator
References
Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas. [2021]Adoptive cellular therapy (ACT) after lymphodepletive conditioning can induce dramatic clinical responses, but this approach has been largely limited to melanoma due to a lack of reliable methods for expanding tumor-specific lymphocytes from the majority of other solid cancers. We have employed tumor RNA-pulsed dendritic cells (DCs) to reliably expand CD4+ and CD8+ tumor-reactive T lymphocytes for curative ACT in a highly-invasive, chemotherapy- and radiation-resistant malignant glioma model. Curative treatment of established intracranial tumors involved a synergistic interaction between myeloablative (MA) conditioning, adoptively transferred tumor-specific T cells, and tumor RNA-pulsed DC vaccines. Hematopoietic stem cells (HSCs), administered for salvage from MA conditioning, rapidly migrated to areas of intracranial tumor growth and facilitated the recruitment of tumor-specific lymphocytes through HSC-elaborated chemokines and enhanced immunologic rejection of intracranial tumors during ACT. Furthermore, HSC transplant under non-myeloablative (NMA) conditions also enhanced immunologic tumor rejection, indicating a novel role for the use of HSCs in the immunologic treatment of malignant gliomas and possibly other solid tumors.
Preclinical full-scale evaluation of dendritic cells transfected with autologous tumor-mRNA for melanoma vaccination. [2020]Most cancer vaccines to date have made use of common tumor antigens or allogenic cancer cell lines. The majority of tumor antigens may, however, be unique patient-specific antigens. Dendritic cells (DCs) are the most potent antigen-presenting cells known. The present report is a full-scale preclinical evaluation of autologous DCs transfected with autologous tumor-mRNA (tDCs) for vaccination in malignant melanoma. By using autologous tumor-mRNA, we intend to make the DCs present a broad spectrum of tumor-associated antigens relevant to each individual patient. Previously, we have described effective methods for mRNA-transfection into DCs by square-wave electroporation and for generating large numbers of DCs. Here, we demonstrate the ability of tDCs, made under full-scale vaccine conditions, to generate in vitro T-cell responses specific for antigens encoded by the transfected tumor-mRNA. T-cell proliferation assays demonstrated tDC-specific responses for all six patients tested. Responses were further studied by IFNgamma ELISPOT and Bioplex cytokine assays (two patients) and by experiments on isolated CD4(+) and CD8(+) T cells, including HLA-blockage (one patient). Moreover, we describe the results of extensive tumor-RNA analysis using Agilent Bioanalyser, a method that we have implemented in the clinical protocol. Based on this preclinical evaluation, a vaccine trial has been started.
[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.
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.
Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles. [2021]While RNA-pulsed dendritic cell (DC) vaccines have shown promise, the advancement of cellular therapeutics is fraught with developmental challenges. To circumvent the challenges of cellular immunotherapeutics, we developed clinically translatable nanoliposomes that can be combined with tumor-derived RNA to generate personalized tumor RNA-nanoparticles (NPs) with considerable scale-up capacity. RNA-NPs bypass MHC restriction, are amenable to central distribution, and can provide near immediate immune induction. We screened commercially available nanoliposomal preparations and identified the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) as an efficient mRNA courier to antigen-presenting cells (APCs). When administered intravenously, RNA-NPs mediate systemic activation of APCs in reticuloendothelial organs such as the spleen, liver, and bone marrow. RNA-NPs increase percent expression of MHC class I/II, B7 co-stimulatory molecules, and maturation markers on APCs (all vital for T-cell activation). RNA-NPs also increase activation markers on tumor APCs and elicit potent expansion of antigen-specific T-cells superior to peptide vaccines formulated in complete Freund's adjuvant. We demonstrate that both model antigen-encoding and physiologically-relevant tumor-derived RNA-NPs expand potent antitumor T-cell immunity. RNA-NPs were shown to induce antitumor efficacy in a vaccine model and functioned as a suitable alternative to DCs in a stringent cellular immunotherapy model for a radiation/temozolomide resistant invasive murine high-grade glioma. Although cancer vaccines have suffered from weak immunogenicity, we have advanced a RNA-NP formulation that systemically activates host APCs precipitating activated T-cell frequencies necessary to engender antitumor efficacy. RNA-NPs can thus be harnessed as a more feasible and effective immunotherapy to re-program host-immunity.
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.
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.
[Tumor RNA introduction into dendritic cells and Epstein-Barr virus transformed B cells]. [2006]In induction of autologous tumor-reactive antigen (TRA) specific cytotoxic T lymphocytes (CTLs) using antigenic peptides and cultured dendritic cells (DCs), identification of the adequate tumor antigens and HLA typing of individuals are required. These restrictions have promoted the use of tumor cells themselves, including tumor cell lysates and tumor cell-DC fusion cells. However, it is very difficult to obtain enough tumor cells for treatment in the clinical setting. We have studied the use of RNA derived from tiny tumor cells. RNA was reverse-transcribed into cDNA, after which T7-amplification and in vitro transcription were carried out. The amplified RNA was successfully electroporated into DCs, and polyclonal polyspecific CTLs could be generated. EBV transformed B cells were also good candidates to be electroporated with the RNA. This suggests that tumor RNA amplification followed by introduction into DCs or EBV transformed B cells is a feasible and practical method to prepare potent APCs.
Massive clonal expansion of medulloblastoma-specific T cells during adoptive cellular therapy. [2023]In both human and murine systems, we have developed an adoptive cellular therapy platform against medulloblastoma and glioblastoma that uses dendritic cells pulsed with a tumor RNA transcriptome to expand polyclonal tumor-reactive T cells against a plurality of antigens within heterogeneous brain tumors. We demonstrate that peripheral TCR Vβ repertoire analysis after adoptive cellular therapy reveals that effective response to adoptive cellular therapy is concordant with massive in vivo expansion and persistence of tumor-specific T cell clones within the peripheral blood. In preclinical models of medulloblastoma and glioblastoma, and in a patient with relapsed medulloblastoma receiving adoptive cellular therapy, an early and massive expansion of tumor-reactive lymphocytes, coupled with prolonged persistence in the peripheral blood, is observed during effective therapeutic response to immunotherapy treatment.