Senza5 CART5 for T-Cell Lymphoma

(VIPER101 Trial)

Recruiting at 1 trial location

Overseen By Vittoria Biotherapeutics

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Vittoria Biotherapeutics

Must not be taking: Steroids, Immunosuppressants, Alemtuzumab, others

Disqualifiers: Pregnancy, HIV, Uncontrolled infection, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Varies based on dose level

30 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not allow the use of systemic steroids or immunosuppressant medications, and you must not have had certain treatments like monoclonal antibody therapy within 4 weeks or chemotherapy within 2 weeks before starting the trial. It's best to discuss your current medications with the trial team to see if they are allowed.

What data supports the effectiveness of the treatment Senza5 CART5 for T-Cell Lymphoma?

Research on similar treatments, like CD5 CAR T-cells, shows they can effectively target and destroy cancerous T-cells in lab settings and animal models, suggesting potential for treating T-cell lymphomas. ^{1 2 3 4 5}

What safety data exists for Senza5 CART5 (also known as VIPER-101) in humans?

Research on similar CAR-T therapies targeting CD5 and CD7 shows potential safety concerns due to fratricide (self-destruction of T-cells), but modifications like CRISPR/Cas9 gene knockout and safety switches have been explored to address these issues. These studies suggest that with these modifications, the therapies can be safe and effective in treating T-cell malignancies. ^{2 4 6 7 8}

How is the Senza5 CART5 treatment different from other treatments for T-cell lymphoma?

Senza5 CART5 is unique because it targets the CD5 protein on T-cells using a special type of CAR-T cell therapy that reduces the risk of the therapy attacking itself (fratricide) and enhances its effectiveness against T-cell lymphoma. ^{2 4 7 9 10}

What is the purpose of this trial?

This is an open-label phase I study to determine the safety and recommended phase 2 dose (RP2D) of Senza5 CART5 cells in patients with relapsed or refractory CD5 positive nodal T cell NHL. RP2D will be based on the safety, tolerability, pharmacokinetics, and preliminary efficacy of Senza5 CART5 cells. This trial will evaluate up to 5 dose levels using the Bayesian Optimal Interval (BOIN) design enrolling 3 patients in each cohort to assess safety and achieve therapeutic levels so that the RP2D of Senza5 CART5 cells given as a single IV infusion can be determined.

Eligibility Criteria

This trial is for people with a type of blood cancer called T-cell Non-Hodgkin Lymphoma that has come back or hasn't responded to treatment. Participants must have CD5 positive nodal disease, meaning the cancer affects certain immune cells and lymph nodes.

Inclusion Criteria

No circulating CD5+ malignant cells identified by peripheral blood flow cytometry must be present

My lymphoma is CD5 positive and has returned or is not responding to treatment.

I have a tumor or cancer in the bone, marrow, or skin that can be measured.

Exclusion Criteria

I am HIV positive.

Any uncontrolled active medical disorder that would preclude participation as outlined

I do not have any active inflammatory or autoimmune diseases.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Senza5 CART5 cells with or without standard of care lymphodepletion

Varies based on dose level

Multiple visits for dose administration and monitoring

Follow-up

Participants are monitored for safety, tolerability, and efficacy of Senza5 CART5 cells

12 months

Regular visits for safety and efficacy assessments

Treatment Details

Interventions

• Senza5 CART5

Trial Overview The study tests Senza5 CART5, a new therapy involving engineered immune cells designed to target and kill lymphoma cells. It's an early-phase trial aiming to find the safest dose level. Patients are grouped into cohorts; each group receives increasing doses based on safety results.

Participant Groups

Group I: Senza5 CART5 without standard of care lymphodepletion Experimental Treatment 1 Intervention

Four treatment arms in patients are lymphopenic into the corresponding dose level.

Group II: Senza5 CART5 with standard of care lymphodepletion Experimental Treatment 1 Intervention

Four treatment arms with Standard of Care Lymphodepletion: Fludarabine 25mg/m2 IV for 3 days Cyclophosphamide 250mg/m2 IV for 3 days

Who Is Running the Clinical Trial?

Vittoria Biotherapeutics

Lead Sponsor

Trials

1

Recruited

30+

University of Pennsylvania

Collaborator

Trials

2,118

Recruited

45,270,000+

Findings from Research

In a study of 118 patients with cutaneous T-cell lymphomas (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS), the overall survival for MF patients was 17.7 years, while SS patients had a median survival of 3.5 years, indicating significant differences in outcomes based on the type of CTCL.

The most common treatments for MF included low-dose methotrexate and interferon-alpha, while SS patients often received bexarotene and extracorporeal photopheresis, highlighting the need for more innovative therapies to be integrated into earlier treatment lines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Analysis of 118 Patients With Cutaneous T-Cell Lymphomas: A Single-Center Experience. Polgárová, K., Polívka, J., Kodet, O., et al.[2022]

T cells modified with a CD5 CAR showed strong ability to target and destroy malignant T-cell lines and primary tumors in laboratory tests, indicating their potential effectiveness against T-cell malignancies.

In animal models of T-cell acute lymphoblastic leukemia (T-ALL), CD5 CAR T cells significantly improved tumor control and survival, suggesting promising outcomes for future clinical applications, especially with the added safety of a CD52 switch to manage CAR cell persistence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of an Anti-CD5 Directed CAR T-Cell against T-Cell Malignancies. Wada, M., Zhang, H., Fang, L., et al.[2021]

In a study of 18 children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), reinfusion with a second chimeric antigen receptor T-cell (CART2) product led to a 38.9% objective response rate, with some patients achieving minimal residual disease (MRD) negative complete remission (CR).

Intensified lymphodepletion before CART2 infusion was associated with better CART2 expansion and higher response rates, suggesting that modifying pre-treatment strategies may enhance the effectiveness of CART2 in patients who did not respond adequately to the first infusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of second CAR-T (CART2) infusion limited by poor CART expansion and antigen modulation. Holland, EM., Molina, JC., Dede, K., et al.[2022]

CD5-targeted CAR T cells show limited fratricide, allowing for long-term expansion and effective elimination of T-cell malignancies like T-ALL and T-cell lymphoma in laboratory settings.

In mouse models, these CD5 CAR T cells significantly inhibited disease progression, highlighting their potential as a therapeutic option for patients with T-cell neoplasms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A T-cell-directed chimeric antigen receptor for the selective treatment of T-cell malignancies. Mamonkin, M., Rouce, RH., Tashiro, H., et al.[2022]

In a phase IIa trial involving 11 patients with relapsed or refractory CD20+ B-cell lymphoma, the use of CAR-modified T cells (CART-20) resulted in an impressive overall response rate of 81.8%, with 6 complete remissions and 3 partial remissions, indicating strong efficacy.

The treatment was well-tolerated with no severe toxicity reported, and the median progression-free survival was over 6 months, suggesting that CART-20 is a promising option for patients with difficult-to-treat lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of CD20-directed Chimeric Antigen Receptor-modified T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an early phase IIa trial report. Zhang, WY., Wang, Y., Guo, YL., et al.[2021]

The study developed a bispecific CAR-T therapy targeting CD5 and CD7, which showed strong antitumor activity against T-cell malignancies while preventing fratricide among CAR-T cells by using CRISPR/Cas9 to knockout these target genes.

Tandem CAR constructs were found to be more effective than dual CARs in preventing tumor escape in heterogeneous leukemic cells, highlighting their potential for meaningful clinical efficacy and safety in treating refractory T-cell leukemia/lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cells expressing CD5/CD7 bispecific chimeric antigen receptors with fully human heavy-chain-only domains mitigate tumor antigen escape. Dai, Z., Mu, W., Zhao, Y., et al.[2022]

CD5-targeting CAR-T therapy has the potential to effectively treat T cell malignancies, which are often difficult to manage due to high recurrence and mortality rates, especially since CD5 is expressed in about 85% of these cancers.

The development of a biepitopic CAR (FHVH3/VH1) that avoids fratricide in CAR-T cells through CD5 knockout shows enhanced and longer-lasting efficacy in both lab tests and animal models, making it a promising candidate for future clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The rational development of CD5-targeting biepitopic CARs with fully human heavy-chain-only antigen recognition domains. Dai, Z., Mu, W., Zhao, Y., et al.[2022]

The novel anti-CD37 CAR T-cell therapy shows significant promise in treating B-cell non-Hodgkin lymphomas and chronic lymphocytic leukemia, demonstrating effective activation and cytotoxic activity in both in vitro and in vivo models, including patient-derived xenografts.

This therapy can be combined with anti-CD19 CAR T cells to create dual-specific CAR T cells, enhancing the ability to target multiple antigens and potentially improving treatment outcomes for patients with lymphoid malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD37 chimeric antigen receptor T cells are active against B- and T-cell lymphomas. Scarfò, I., Ormhøj, M., Frigault, MJ., et al.[2022]

Anti-CXCR5 CAR-T cell therapy effectively targets both B cell Non-Hodgkin's lymphoma (B-NHLs) and follicular T helper (Tfh) cells, showing greater potency in eradicating these cells compared to traditional CD19 CAR-T cells in laboratory studies.

In murine models, anti-CXCR5 CAR-T cells specifically deplete both malignant B cells and Tfh cells without causing harmful effects on normal tissues, suggesting a safe and effective treatment strategy for nodal B-NHLs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin's lymphoma and tumor-supportive follicular T helper cells. Bunse, M., Pfeilschifter, J., Bluhm, J., et al.[2021]

CD5-targeting CAR-T cells show strong potential against T cell acute lymphoblastic leukemia (T-ALL), especially when optimized with a CH2CH3 hinge region, which enhances their ability to kill cancer cells both in vitro and in vivo.

While initial CAR designs with 4-1BB or CD28 costimulatory domains showed specific cytotoxicity, they did not improve survival in T-ALL models, highlighting the importance of structural optimization for better therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A CH2CH3 hinge region enhances the cytotoxicity of anti-CD5 CAR-T cells targeting T cell acute lymphoblastic leukemia. Wu, H., Yu, Y., Zhao, Y., et al.[2023]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Retrospective Analysis of 118 Patients With Cutaneous T-Cell Lymphomas: A Single-Center Experience. [2022]

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

Characterization of an Anti-CD5 Directed CAR T-Cell against T-Cell Malignancies. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Efficacy of second CAR-T (CART2) infusion limited by poor CART expansion and antigen modulation. [2022]

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

A T-cell-directed chimeric antigen receptor for the selective treatment of T-cell malignancies. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Treatment of CD20-directed Chimeric Antigen Receptor-modified T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an early phase IIa trial report. [2021]

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

T cells expressing CD5/CD7 bispecific chimeric antigen receptors with fully human heavy-chain-only domains mitigate tumor antigen escape. [2022]

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

The rational development of CD5-targeting biepitopic CARs with fully human heavy-chain-only antigen recognition domains. [2022]

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

Anti-CD37 chimeric antigen receptor T cells are active against B- and T-cell lymphomas. [2022]

9. England pubmed.ncbi.nlm.nih.gov

CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin's lymphoma and tumor-supportive follicular T helper cells. [2021]

10. Netherlands pubmed.ncbi.nlm.nih.gov

A CH2CH3 hinge region enhances the cytotoxicity of anti-CD5 CAR-T cells targeting T cell acute lymphoblastic leukemia. [2023]