CAR-T Cells +/− Radiation for Prostate Cancer
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Male
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: City of Hope Medical Center
Must not be taking: Systemic steroids
Disqualifiers: Arrhythmia, Optic neuritis, Stroke, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This phase Ib trial tests the safety, side effects, and best dose of autologous anti-prostate stem cell antigen (PSCA)-chimeric antigen receptor (CAR)-4-1BB/TCRzeta-CD19t-expressing T-lymphocytes (PSCA-CAR T cells), plus or minus radiation, in treating patients with castration-resistant prostate cancer that has spread from where it first started (primary site) to other places in the body (metastatic). Castration-resistant prostate cancer continues to grow and spread despite the surgical removal of the testes or medical intervention to block androgen production. CAR T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Radiation therapy uses high energy x-rays to kill cancer cells and shrink tumors. Giving PSCA-targeting CAR T-cells, with or without radiation, may kill more tumor cells in men with castration-resistant prostate cancer.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but it does exclude those using systemic steroids or chronic immunosuppressants. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the treatment CAR-T Cells +/− Radiation for Prostate Cancer?
Research shows that CAR-T cells targeting the prostate stem cell antigen (PSCA) have demonstrated strong anti-tumor activity in prostate cancer models, with improved selectivity and persistence when using a specific signaling domain. Additionally, CAR-T cell therapy has shown promise in treating solid tumors, including prostate cancer, by delaying tumor growth and prolonging survival in experimental models.
12345Is CAR-T cell therapy targeting PSCA safe for humans?
Research on CAR-T cell therapy targeting PSCA for prostate cancer shows promising results in mice, with effective tumor targeting and minimal impact on healthy tissues. However, potential safety concerns exist due to the risk of 'on-target off-tumor' activity, where healthy tissues expressing the targeted antigen might be affected.
12346What makes the CAR-T cell treatment for prostate cancer unique?
This CAR-T cell treatment is unique because it targets the prostate stem cell antigen (PSCA), which is commonly found on prostate cancer cells, and uses a 4-1BB co-stimulatory signaling domain to improve T cell persistence and selectivity, potentially leading to better control of the disease compared to other treatments.
12378Eligibility Criteria
This trial is for men aged 18+ with metastatic castration-resistant prostate cancer that has spread and shows PSCA protein presence. They must have adequate organ function, no severe allergies to study agents, no active infections or bleeding disorders, not be HIV or hepatitis B/C positive, and agree to birth control measures.Inclusion Criteria
I am 18 years old or older.
Corrected QT interval (QTc) =< 480 ms
My prostate cancer is resistant to hormonal therapy.
+17 more
Exclusion Criteria
I have not had a stroke or brain bleed in the last 6 months.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
I have a history of optic neuritis or other immune-related brain diseases.
+9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Leukapheresis and Lymphodepletion
Patients undergo leukapheresis and lymphodepletion as preparation for CAR T-cell therapy
1-2 weeks
Treatment
Patients receive PSCA-CAR T cells intravenously up to 3 times, with or without radiation therapy
Up to 3 cycles (each cycle is 56 days)
Follow-up
Participants are monitored for safety, effectiveness, and disease response after treatment
Up to 1 year
Long-term Follow-up
Participants are monitored for long-term safety and survival outcomes
Up to 15 years
Participant Groups
The trial tests the safety and optimal dose of modified immune cells (PSCA-CAR T-cells) designed to target prostate cancer cells, given with or without radiation therapy. It aims to see if these treatments can better eliminate tumors in patients whose prostate cancer continues growing despite hormone therapy.
2Treatment groups
Experimental Treatment
Group I: Treatment plan II (PSCA CAR T-cells, radiation)Experimental Treatment8 Interventions
Patients undergo leukapheresis, radiation in 2 doses, and lymphodepletion, and receive PSCA-CAR T cells IV up to 3 times on study. Patients undergo bone scan, CT scan, tumor biopsy, and collection of blood, stool, and urine samples throughout the trial.
Group II: Treatment plan I (PSCA CAR T-cells)Experimental Treatment7 Interventions
Patients undergo leukapheresis and lymphodepletion and receive PSCA-CAR T cells IV up to 3 times on study. Patients undergo bone scan, CT scan, tumor biopsy, and collection of blood, stool, and urine samples throughout the trial.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
City of Hope Medical CenterDuarte, CA
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Who Is Running the Clinical Trial?
City of Hope Medical CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer. [2021]Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies.
Systemic treatment with CAR-engineered T cells against PSCA delays subcutaneous tumor growth and prolongs survival of mice. [2021]Adoptive transfer of T cells genetically engineered with a chimeric antigen receptor (CAR) has successfully been used to treat both chronic and acute lymphocytic leukemia as well as other hematological cancers. Experimental therapy with CAR-engineered T cells has also shown promising results on solid tumors. The prostate stem cell antigen (PSCA) is a protein expressed on the surface of prostate epithelial cells as well as in primary and metastatic prostate cancer cells and therefore a promising target for immunotherapy of prostate cancer.
Targeting of tumor cells expressing the prostate stem cell antigen (PSCA) using genetically engineered T-cells. [2021]Curative therapeutic options for minimal residual disease or advanced tumor stages in prostate cancer (PCa) are still missing. Adoptive transfer of cytotoxic T-cells that have been polyclonally rendered tumor-specific by genetic engineering appears to be a promising immunotherapeutic strategy. Among the numerous prostate tissue/tumor antigens identified during the last years, the "prostate stem cell antigen" (PSCA) is an attractive immunotherapeutic target. It is broadly expressed on the surface of primary PCa cells as well as on PCa metastases.
Anti-PSMA CAR-engineered NK-92 Cells: An Off-the-shelf Cell Therapy for Prostate Cancer. [2021]Prostate cancer (PCa) has become the most common cancer among males in Europe and the USA. Adoptive immunotherapy appears a promising strategy to control the advanced stages of the disease by specifically targeting the tumor, in particular through chimeric antigen receptor T (CAR-T) cell therapy. Despite the advancements of CAR-T technology in the treatment of hematological malignancies, solid tumors still represent a challenge. To overcome current limits, other cellular effectors than T lymphocytes are under study as possible candidates for CAR-engineered cancer immunotherapy. A novel approach involves the NK-92 cell line, which mediates strong cytotoxic responses against a variety of tumor cells but has no effect on non-malignant healthy counterparts. Here, we report a novel therapeutic approach against PCa based on engineering of NK-92 cells with a CAR recognizing the human prostate-specific membrane antigen (PSMA), which is overexpressed in prostatic neoplastic cells. More importantly, the potential utility of NK-92/CAR cells to treat PCa has not yet been explored. Upon CAR transduction, NK-92/CAR cells acquired high and specific lytic activity against PSMA-expressing prostate cancer cells in vitro, and also underwent degranulation and produced high levels of IFN-γ in response to antigen recognition. Lethal irradiation of the effectors, a safety measure requested for the clinical application of retargeted NK-92 cells, fully abrogated replication but did not impact on phenotype and short-term functionality. PSMA-specific recognition and antitumor activity were retained in vivo, as adoptive transfer of irradiated NK-92/CAR cells in prostate cancer-bearing mice restrained tumor growth and improved survival. Anti-PSMA CAR-modified NK-92 cells represent a universal, off-the-shelf, renewable, and cost-effective product endowed with relevant potentialities as a therapeutic approach for PCa immunotherapy.
CAR T Cells with a Dominant-Negative TGFβ Receptor Are Safe and Feasible. [2022]PSMA-targeting CAR T cells with a dominant-negative TGFβR show safety and feasibility in prostate cancer.
Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. [2021]Current T-cell engineering approaches redirect patient T cells to tumors by transducing them with antigen-specific T-cell receptors (TCRs) or chimeric antigen receptors (CARs) that target a single antigen. However, few truly tumor-specific antigens have been identified, and healthy tissues that express the targeted antigen may undergo T cell-mediated damage. Here we present a strategy to render T cells specific for a tumor in the absence of a truly tumor-restricted antigen. T cells are transduced with both a CAR that provides suboptimal activation upon binding of one antigen and a chimeric costimulatory receptor (CCR) that recognizes a second antigen. Using the prostate tumor antigens PSMA and PSCA, we show that co-transduced T cells destroy tumors that express both antigens but do not affect tumors expressing either antigen alone. This 'tumor-sensing' strategy may help broaden the applicability and avoid some of the side effects of targeted T-cell therapies.
CART cell therapy for prostate cancer: status and promise. [2020]In recent years, the, chimeric antigen receptor T (CAR-T) cell therapy as an adoptive immunotherapy has received great attention and made great breakthroughs. CAR-T cells show great specificity, targeting, and less major histocompatibility complex restriction in tumor immunotherapy, significantly different from traditional T cells. In spite of the progress of CART-T technology in the treatment of lymphoma, leukemia, and other blood system tumor, there are still many difficulties in the treatment of solid tumors by CAR-T technology. In this review, we will make a brief summary of the present situation of CAR-T cells in the treatment of prostate cancer, and discuss the promise of the application of this technology to prostate cancer therapy.
PSMA-Specific CAR-Engineered T Cells for Prostate Cancer: CD28 Outperforms Combined CD28-4-1BB "Super-Stimulation". [2021]Prostate cancer (PCa) is the second leading cause of malignancy-related mortality in males in the Western world. Although treatment like prostatectomy and radiotherapy for localized cancer have good results, similar positive outcomes are not achieved in metastatic PCa. Consequently, these aggressive and metastatic forms of PCa urgently need new methods of treatment. We already described an efficient and specific second-generation (2G) Chimeric Antigen Receptor (CAR) against Prostate Specific Membrane Antigen (PSMA), a glycoprotein overexpressed in prostate cancer and also present on neovasculature of several tumor entities. In an attempt to improve efficacy and in vivo survival of anti-PSMA 2G CAR-T cells, we developed a third generation (3G) CAR containing two costimulatory elements, namely CD28 and 4-1BB co-signaling domains, in addition to CD3ζ. Differently from what described for other 3G receptors, our third generation CAR disclosed an antitumor activity in vitro similar to the related 2G CAR that comprises the CD28 co-signaling domain only. Moreover, the additional costimulatory domain produced detrimental effects, which could be attributed to an increased activation-induced cell death (AICD). Indeed, such "superstimulation" resulted in an exhausted phenotype of CAR-T cells, after prolonged in vitro restimulation, a higher frequency of cell death, and an impairment in yielding sufficient numbers of transgenic T lymphocytes. Thus, the optimal combination of costimulatory domains for CAR development should be assessed cautiously and evaluated case-by-case.