B7-H3CART for Solid Tumors

Overseen By Amy Li

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Stanford University

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: Other malignancy, Brain metastases, Infections, Cardiac disease, others

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

Compensation: Varies

Number of Visits: 8

Duration: 1 day

41 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the manufacturing feasibility and safety of intravenous (IV) administration of B7-H3CART in children and young adult subjects with relapsed and/or refractory solid tumors expressing B7-H3 target using a standard 3+3 dose escalation design.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you must stop all current medications. However, there is a required washout period of at least 2 weeks or 5 half-lives for prior systemic therapies, except for immune checkpoint therapies, which require 5 half-lives. Systemic corticosteroids or immunosuppressive therapies require a one-week washout. Please consult with the trial team for guidance on your specific medications.

What data supports the idea that B7-H3CART for Solid Tumors is an effective treatment?

The available research shows that B7-H3CART has shown promise in treating certain solid tumors. For example, studies have demonstrated that B7-H3CART can control the growth of prostate cancer and other types of cancer like pancreatic, ovarian, and neuroblastoma in lab and animal models. These studies also found that B7-H3CART can work without causing significant side effects. However, the effectiveness of B7-H3CART is still limited, and researchers are exploring ways to improve it, such as combining it with other treatments. ^{1 2 3 4 5}

What safety data exists for B7-H3CART treatment?

Initial trials of B7-H3-targeted CAR-T cell therapies have demonstrated safety, although their efficacy was limited. Studies have shown that B7-H3.CAR-Ts can control tumor growth without evident toxicity in preclinical models. However, the safety profile of CAR-T cell therapy, including potential cutaneous adverse events, continues to evolve, and more data is needed to fully understand the spectrum of possible toxicities. ^{1 4 6 7 8}

Is the treatment B7-H3CART promising for solid tumors?

Yes, B7-H3CART is a promising treatment for solid tumors. It targets a protein called B7-H3, which is found in many solid tumors but not much in normal tissues. This makes it a good target for treatment. Studies have shown that B7-H3CART can control tumor growth in various cancers, including prostate, pancreatic, ovarian, and brain tumors, without causing significant side effects. This suggests it has the potential to be an effective treatment for these types of cancers. ^{1 3 4 5 9}

Research Team

Sneha Ramakrishna, MD

Principal Investigator

Stanford University

Eligibility Criteria

This trial is for children and young adults with solid tumors like sarcoma, neuroblastoma, or osteosarcoma that have come back or didn't respond to previous treatments. The tumors must express a target called B7-H3. Specific eligibility details are not provided but would typically include health status and prior therapies.

Inclusion Criteria

I am between 2 and 25 years old.

My cancer is incurable, has returned or worsened after all treatments.

Availability of evaluable or measurable disease during dose escalation/expansion

Exclusion Criteria

I have had serious heart problems in the last year.

Receiving any other current investigational agents

Severe immediate hypersensitivity reaction to study agents

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion

Participants receive Fludarabine and Cyclophosphamide to prepare for B7-H3CART cell infusion

1 week

Daily visits for 7 days

Treatment

Participants receive a single dose of intravenous B7-H3CART cells

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Treatment Details

Interventions

• B7-H3CART

Trial Overview The study is testing the safety of a new therapy where patients receive an IV dose of genetically engineered T cells (B7-H3CART) designed to attack cancer cells expressing B7-H3. It follows a '3+3' design which means small groups are given increasing doses to find the safest amount.

Participant Groups

Group I: Lymphodepletion Experimental Treatment 1 Intervention

Fludarabine 30 mg/m2 per day IV for 4 days: 5, -4, 3, -2 Cyclophosphamide 500 mg/m2 per day IV for 3 days: -5, -4, -3 Subjects who meet cell infusion eligibility will receive IV B7-H3CART cells on Day 0.

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Crystal Mackall, MD

Lead Sponsor

Trials

6

Recruited

240+

Findings from Research

B7-H3 is a promising target for immunotherapy in solid tumors due to its overexpression in tumors and limited presence in normal tissues, making it a suitable candidate for chimeric antigen receptor (CAR) therapies.

Initial trials of B7-H3-targeted CAR-T cell therapies have shown safety, but their effectiveness has been limited; strategies such as local delivery, enhancing CAR-T cell persistence, and combining with other treatments may improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B7-H3-targeted CAR-T cell therapy for solid tumors. Li, G., Wang, H., Wu, H., et al.[2022]

B7-H3 is widely expressed in various human solid tumors but has limited expression in normal tissues, making it a promising target for CAR T-cell therapy.

Combining B7-H3.CAR T cells with the epigenetic drug SAHA significantly boosts their ability to kill solid cancer cells, suggesting this combination could improve treatment outcomes in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Pan-Histone Deacetylase Inhibitor Enhances the Antitumor Activity of B7-H3-Specific CAR T Cells in Solid Tumors. Lei, X., Ou, Z., Yang, Z., et al.[2022]

B7-H3 is highly expressed in prostate cancer cells and tissues, making it a promising target for immunotherapy, particularly for developing CAR-T cell therapies.

The newly developed B7-H3 CAR-T cells effectively inhibited prostate cancer growth in both laboratory and animal models, demonstrating their potential for clinical application in treating this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B7-H3 specific CAR-T cells exhibit potent activity against prostate cancer. Li, S., Zhang, M., Wang, M., et al.[2023]

B7-H3.CAR-T cells effectively controlled the growth of various cancers, including pancreatic ductal adenocarcinoma, ovarian cancer, and neuroblastoma, in both laboratory and mouse models, indicating their potential as a powerful immunotherapy.

The use of 4-1BB co-stimulation in B7-H3.CAR-T cells led to lower PD-1 expression and enhanced antitumor activity, suggesting a mechanism that could improve the effectiveness of these CAR-T therapies without causing significant toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells. Du, H., Hirabayashi, K., Ahn, S., et al.[2021]

B7-H3 CAR T cells have shown significant antitumor activity in various pediatric solid tumor models, including osteosarcoma and medulloblastoma, indicating their potential as a treatment option for relapsed pediatric malignancies.

The effectiveness of B7-H3 CAR T cells is linked to the density of the B7-H3 antigen on tumor cells, suggesting that this therapy could be selectively effective against tumors with high antigen expression while minimizing effects on normal tissues with lower expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors. Majzner, RG., Theruvath, JL., Nellan, A., et al.[2021]

Low-affinity CAR-T cells targeting the oncofetal antigen glypican 3 (GPC3) effectively kill tumor cells without causing toxicity to normal tissues, unlike high-affinity CAR-T cells that induce harmful side effects due to on-target, off-tumor binding.

An innovative approach using anti-TNF-α antibody therapy allows for the selective elimination of early activated CAR-T cells, helping to manage toxicity while maintaining tumor control, demonstrating a potential method to enhance the safety of CAR-T therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rational design of chimeric antigen receptor T cells against glypican 3 decouples toxicity from therapeutic efficacy. Giardino Torchia, ML., Gilbreth, R., Merlino, A., et al.[2022]

Chimeric antigen receptor T-cell therapy is a promising immunotherapy that shows effective results in treating cancers that have not responded to other treatments, as it uses genetically engineered T cells to target and destroy tumor cells.

There is a need for more information on the safety profile of this therapy, particularly regarding skin-related side effects, to improve early recognition and management of these adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cutaneous manifestations of chimeric antigen receptor T-cell therapy: An introduction for dermatologists. Nusbaum, KB., Dulmage, B., Choi, JN., et al.[2022]

CAR-modified NK-92MI cells targeting the B7-H3 molecule showed significantly enhanced ability to kill B7-H3-positive tumor cells, indicating improved efficacy in cancer treatment.

In mouse models of non-small cell lung cancer, these engineered NK cells not only inhibited tumor growth but also extended the survival of the mice, supporting their potential use in adoptive cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting B7-H3 Immune Checkpoint With Chimeric Antigen Receptor-Engineered Natural Killer Cells Exhibits Potent Cytotoxicity Against Non-Small Cell Lung Cancer. Yang, S., Cao, B., Zhou, G., et al.[2020]

B7-H3 CAR-T cells, engineered to target a protein commonly found in solid tumors, demonstrated strong antitumor activity in both laboratory tests and mouse models, suggesting their potential effectiveness against advanced solid tumors.

The addition of PD-1 decoy receptors to these CAR-T cells enhanced their persistence and antitumor activity, indicating a promising strategy for improving CAR-T therapy outcomes in challenging solid tumor environments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B7-H3 specific T cells with chimeric antigen receptor and decoy PD-1 receptors eradicate established solid human tumors in mouse models. Huang, B., Luo, L., Wang, J., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

B7-H3-targeted CAR-T cell therapy for solid tumors. [2022]

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

A Pan-Histone Deacetylase Inhibitor Enhances the Antitumor Activity of B7-H3-Specific CAR T Cells in Solid Tumors. [2022]

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

B7-H3 specific CAR-T cells exhibit potent activity against prostate cancer. [2023]

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

Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells. [2021]

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

CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Rational design of chimeric antigen receptor T cells against glypican 3 decouples toxicity from therapeutic efficacy. [2022]

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

Cutaneous manifestations of chimeric antigen receptor T-cell therapy: An introduction for dermatologists. [2022]

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

Targeting B7-H3 Immune Checkpoint With Chimeric Antigen Receptor-Engineered Natural Killer Cells Exhibits Potent Cytotoxicity Against Non-Small Cell Lung Cancer. [2020]

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

B7-H3 specific T cells with chimeric antigen receptor and decoy PD-1 receptors eradicate established solid human tumors in mouse models. [2022]