CAR-T Cells +/− Radiation for Prostate Cancer

Age: 18+

Sex: Male

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Systemic steroids

Disqualifiers: Arrhythmia, Optic neuritis, Stroke, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 3 cycles (each cycle is 56 days)

21 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{1 2 3 4 6}

What 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. ^{1 2 3 7 8}

Research Team

Tanya Dorff, MD

Principal Investigator

City of Hope Medical Center

Eligibility 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

Corrected QT interval (QTc) =< 480 ms

My prostate cancer is resistant to hormonal therapy.

Seronegative for HIV antigen (Ag)/antibody (Ab) combo, hepatitis C virus (HCV), active hepatitis B virus (HBV), and syphilis

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.

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

Treatment Details

Interventions

• Autologous Anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T-lymphocytes
• External Beam Radiation Therapy

Trial Overview 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.

Participant Groups

Group I: Treatment plan II (PSCA CAR T-cells, radiation) Experimental Treatment 8 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 Treatment 7 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.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

The study found that using a 4-1BB co-stimulatory signaling domain in CAR T cells targeting prostate cancer leads to better selectivity for tumor cells with high antigen density and reduces T cell exhaustion, compared to the CD28 domain.

In patient-derived models of bone-metastatic prostate cancer, 4-1BB-containing CAR T cells showed superior persistence and effectiveness in controlling the disease, highlighting the importance of co-stimulation in CAR T cell therapy for solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer. Priceman, SJ., Gerdts, EA., Tilakawardane, D., et al.[2021]

The study developed a third-generation CAR T cell targeting the prostate stem cell antigen (PSCA), which showed specific immune responses and effective tumor cell killing in laboratory tests.

In mouse models, treatment with PSCA-CAR T cells significantly delayed tumor growth and improved survival, suggesting potential for this therapy in treating prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic treatment with CAR-engineered T cells against PSCA delays subcutaneous tumor growth and prolongs survival of mice. Hillerdal, V., Ramachandran, M., Leja, J., et al.[2021]

A new chimeric T-cell receptor (TCR) targeting the prostate stem cell antigen (PSCA) was successfully developed, showing promise for treating prostate cancer by activating cytotoxic T-cells against PSCA-positive tumor cells.

This innovative approach involves genetic engineering of T-cells to enhance their ability to recognize and attack prostate cancer cells, potentially offering a new immunotherapeutic strategy for patients with minimal residual disease or advanced tumor stages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting of tumor cells expressing the prostate stem cell antigen (PSCA) using genetically engineered T-cells. Morgenroth, A., Cartellieri, M., Schmitz, M., et al.[2021]

Engineering NK-92 cells with a CAR that targets the prostate-specific membrane antigen (PSMA) allows these cells to effectively kill prostate cancer cells while sparing healthy cells, demonstrating strong potential for targeted therapy.

In mouse models, irradiated NK-92/CAR cells not only inhibited tumor growth but also improved survival rates, suggesting that this approach could be a promising and safe immunotherapy for advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PSMA CAR-engineered NK-92 Cells: An Off-the-shelf Cell Therapy for Prostate Cancer. Montagner, IM., Penna, A., Fracasso, G., et al.[2021]

The study demonstrates that PSMA-targeting CAR T cells, which are engineered to include a dominant-negative TGFβ receptor, are safe and feasible for use in treating prostate cancer.

This approach suggests a promising strategy for enhancing the effectiveness of CAR T cell therapy in prostate cancer patients, potentially improving their treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cells with a Dominant-Negative TGFβ Receptor Are Safe and Feasible. [2022]

A novel T-cell engineering strategy allows T cells to target tumors by using a combination of a chimeric antigen receptor (CAR) and a chimeric costimulatory receptor (CCR), enabling them to specifically attack tumors expressing both targeted antigens, PSMA and PSCA.

This approach minimizes damage to healthy tissues by ensuring that T cells only activate and destroy tumors that express both antigens, potentially reducing side effects associated with traditional T-cell therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Kloss, CC., Condomines, M., Cartellieri, M., et al.[2021]

CAR-T cell therapy has shown significant advancements in treating blood cancers like lymphoma and leukemia due to its high specificity and targeting capabilities, which differ from traditional T cell therapies.

Despite these successes, the application of CAR-T technology in treating solid tumors, such as prostate cancer, still faces many challenges, highlighting the need for further research and development in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CART cell therapy for prostate cancer: status and promise. Yu, H., Pan, J., Guo, Z., et al.[2020]

A third-generation Chimeric Antigen Receptor (CAR) targeting Prostate Specific Membrane Antigen (PSMA) was developed to enhance the efficacy of CAR-T cell therapy for metastatic prostate cancer, but it showed similar in vitro antitumor activity to a second-generation CAR with only one costimulatory domain.

The addition of a second costimulatory domain in the third-generation CAR led to increased activation-induced cell death and an exhausted phenotype in CAR-T cells, suggesting that more costimulatory signals may not always improve treatment outcomes and should be carefully evaluated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PSMA-Specific CAR-Engineered T Cells for Prostate Cancer: CD28 Outperforms Combined CD28-4-1BB "Super-Stimulation". Zuccolotto, G., Penna, A., Fracasso, G., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Systemic treatment with CAR-engineered T cells against PSCA delays subcutaneous tumor growth and prolongs survival of mice. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Targeting of tumor cells expressing the prostate stem cell antigen (PSCA) using genetically engineered T-cells. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Anti-PSMA CAR-engineered NK-92 Cells: An Off-the-shelf Cell Therapy for Prostate Cancer. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

CAR T Cells with a Dominant-Negative TGFβ Receptor Are Safe and Feasible. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. [2021]

7. New Zealand pubmed.ncbi.nlm.nih.gov

CART cell therapy for prostate cancer: status and promise. [2020]

8. Switzerland pubmed.ncbi.nlm.nih.gov

PSMA-Specific CAR-Engineered T Cells for Prostate Cancer: CD28 Outperforms Combined CD28-4-1BB "Super-Stimulation". [2021]