B7-H3CART for Solid Tumors

Recruiting in Palo Alto (17 mi)

Overseen by Sneha Ramakrishna, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Stanford University

Must not be taking: Corticosteroids, Immunosuppressants

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

No Placebo Group

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}

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

Trial 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 (CAR T-cell Therapy)

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.

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Stanford University Palo Alto, CA

Who Is Running the Clinical Trial?

Stanford University Lead Sponsor

References

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

B7-H3-targeted CAR-T cell therapy for solid tumors. [2022] Since B7-H3 is overexpressed or amplified in many types of solid tumors with a restricted expression in the normal tissues, it has been an emerging immunotherapeutic target for solid tumors. This review will focus on the structural designs of developing chimeric antigen receptors (CARs) targeting B7-H3. The expression, receptor, and function of the B7-H3, as well as a short overview of B7-H3-targeted monoclonal antibody therapy, are discussed. Finally, a detailed summary of B7-H3 redirected CAR-T and CAR-NK cell approaches utilized in preclinical models and currently ongoing or completed clinical trials are presented. It has been demonstrated that B7-H3-targeted CAR-based cell therapies were safe in initial trials, but their efficacy was limited. Employing the local delivery routes, the introduction of novel modifications promoting CAR-T persistence, and combined treatment with other standard therapies could improve the efficacy of B7-H3-targeted CAR-T cell therapy against solid tumors.

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] The limited efficacy of chimeric antigen receptor (CAR) T-cell therapies with solid malignancies prompted us to test whether epigenetic therapy could enhance the antitumor activity of B7-H3.CAR T cells with several solid cancer types.

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

B7-H3 specific CAR-T cells exhibit potent activity against prostate cancer. [2023] B7-H3 is an attractive target for immunotherapy because of its high expression across multiple solid tumors, including prostate cancer, and restricted expression in normal tissues. Among various types of tumor immunotherapy, chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable success in hematological tumors. However, the potency of CAR-T cell therapy in solid tumors is still limited. Here, we examined the expression of B7-H3 in prostate cancer tissues and cells and developed a second-generation CAR that specifically targets B7-H3 and CD28 as costimulatory receptor to explore its tumoricidal potential against prostate cancer in vitro and in vivo. The high expression of B7-H3 was detected on both the surface of PC3, DU145 and LNCaP cells and prostate cancer tissues. B7-H3 CAR-T cells efficiently controlled the growth of prostate cancer in an antigen-dependent manner in vitro and in vivo. Moreover, tumor cells could induce the proliferation of CAR-T cells and the release of high levels of cytokines of IFN-γ and TNF-α in vitro. Results demonstrated that B7-H3 is a potential target for prostate cancer therapy that supports the clinical development of B7-H3 specific CAR-T cells for prostate cancer.

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] The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4-1BB co-stimulation promotes lower PD-1 expression in B7-H3.CAR-Ts, and superior antitumor activity when targeting tumor cells that constitutively expressed PD-L1. We took advantage of the cross-reactivity of the B7-H3.CAR with murine B7-H3, and found that B7-H3.CAR-Ts significantly controlled tumor growth in a syngeneic tumor model without evident toxicity. These findings support the clinical development of B7-H3.CAR-Ts.

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] Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T-cell therapy of pediatric solid tumors, including those arising in the central nervous system.

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

Rational design of chimeric antigen receptor T cells against glypican 3 decouples toxicity from therapeutic efficacy. [2022] Chimeric antigen receptor (CAR) T cell therapy has yielded impressive clinical results in hematological malignancies and is a promising approach for solid tumor treatment. However, toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, is a concern hampering its broader use.

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

Cutaneous manifestations of chimeric antigen receptor T-cell therapy: An introduction for dermatologists. [2022] Chimeric antigen receptor T-cell therapy is an emerging immunotherapy with promising efficacy for the treatment of previously refractory or relapsed malignancies. As a personalized medicine approach, T cells are genetically engineered to express a receptor designed to bind a specific tumor antigen, leading to selective immune-mediated destruction of tumor cells. Due to the novelty of chimeric antigen receptor T-cell therapy, the safety profile continues to evolve with limited information currently available on cutaneous adverse events. Improved understanding of the spectrum of cutaneous adverse events may facilitate earlier recognition and appropriate management of these toxicities. To explore this knowledge gap, we discuss the available case reports and clinical trial results of cutaneous reactions associated with chimeric antigen receptor T-cell therapy.

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] Chimeric antigen receptor (CAR)-modified natural killer (NK) cell therapy represents a kind of promising anti-cancer treatment because CAR renders NK cells activation and recognition specificity toward tumor cells. An immune checkpoint molecule, B7-H3, plays an inhibitory role in modulation of NK cells. To enhance NK cell functions, we generated NK-92MI cells carrying anti-B7-H3 CAR by lentiviral transduction. The expression of anti-B7-H3 CAR significantly enhanced the cytotoxicity of NK-92MI cells against B7-H3-positive tumor cells. In accordance with enhanced cytotoxicity, the secretions of perforin/granzyme B and expression of CD107a were highly elevated in anti-B7-H3 CAR-NK-92MI cells. Moreover, compared to unmodified NK-92MI cells, anti-B7-H3 CAR-NK-92MI cells effectively limited tumor growth in mouse xenografts of non-small cell lung cancer and significantly prolonged the survival days of mice. This study provides the rationale and feasibility of B7-H3-specific CAR-NK cells for application in adoptive cancer immunotherapy.

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] The application of chimeric antigen receptor (CAR)-T cell therapy in patients with advanced solid tumors remains a significant challenge. Simultaneously targeting antigen and the solid tumor microenvironment are two major factors that greatly impact CAR-T cell therapy outcomes. In this study, we engineered CAR-T cells to specifically target B7-H3, a protein commonly found in solid human tumors, using a single-chain variable fragment (scFv) derived from an anti-B7-H3 monoclonal antibody. We tested the antitumor activity of B7-H3 CAR-T cells in mouse models with solid human tumors and determined that B7-H3 CAR-T cells exhibited potent antitumor activity against B7-H3+ tumor cells in vitro and in vivo. In addition, PD-1 decoy receptors were engineered to include extracellular PD-1 fused to the intracellular stimulatory domain of either CD28 or IL-7 receptor, respectively, which were then introduced into B7-H3 CAR-T cells. As a result, these newly modified, superior CAR-T cells exhibited more persistent antitumor activity in B7-H3+/B7-H1+ tumors in vivo. Our findings indicate that B7-H3 specific CAR-T cells have the potential to treat multiple types of advanced solid tumors.