Modified Virus and Immunotherapy for T-Cell Lymphoma

Recruiting at 1 trial location

Overseen By Clinical Trials Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Mayo Clinic

Must not be taking: Chemotherapy, Immunotherapy, Experimental agents

Disqualifiers: Active infection, Hepatitis, Cardiac disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 2 years

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the best dose and side effects of recombinant vesicular stomatitis virus (VSV) carrying the human (h) sodium iodide symporter (NIS) and Interferon (IFN) beta (β) genes (VSV-hIFNβ-NIS) in combination with ipilimumab and cemiplimab in patients with T-cell lymphoma. A virus, called VSV-hIFNβ-NIS, which has been changed in a certain way, may be able to kill cancer cells without damaging normal cells. Immunotherapy with ipilmumab and cemiplimab may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread.

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

The trial protocol does not specify if you need to stop your current medications. However, you must not have had chemotherapy within 2 weeks or immunotherapy within 4 weeks before joining. It's best to discuss your specific medications with the trial team.

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

Research shows that interleukin-12 (a protein that helps boost the immune system) therapy can lead to a significant response in cutaneous T-cell lymphoma, with about 50% of patients experiencing lesion regression. Additionally, interferon beta, when applied to skin lesions, has shown effectiveness in treating malignant lymphoma, suggesting potential benefits for similar treatments. ^{1 2 3 4 5}

Is cemiplimab generally safe for humans?

Cemiplimab has been shown to have an acceptable safety profile in clinical trials for advanced cutaneous squamous cell carcinoma, with most side effects being manageable with appropriate treatment or stopping the medication. ^{6 7 8 9 10}

What makes the treatment for T-Cell Lymphoma using Cemiplimab, Ipilimumab, and a modified virus unique?

This treatment is unique because it combines immunotherapy drugs (Cemiplimab and Ipilimumab) with a modified virus (Recombinant Vesicular Stomatitis Virus) that is designed to boost the immune system's ability to fight cancer cells, offering a novel approach compared to traditional therapies. ^{2 3 4 11 12}

Research Team

Kah Whye Peng, PhD

Principal Investigator

Mayo Clinic in Rochester

Nora Bennani, MD

Principal Investigator

Mayo Clinic in Rochester

Eligibility Criteria

This trial is for patients with various types of T-cell lymphoma, including peripheral T-cell lymphoma and skin lymphomas. Participants should not have a fungal infection or mouth sores. The full eligibility criteria are not provided, but typically include factors like age, health status, and prior treatments.

Inclusion Criteria

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2 times upper limit of normal (ULN) (obtained =< 15 days prior to registration)

Direct bilirubin =< 1.5 x ULN (obtained =< 15 days prior to registration)

Creatinine =< 2.0 mg/dL (obtained =< 15 days prior to registration)

Exclusion Criteria

I am willing and able to undergo treatment aimed at curing my disease.

I do not have any infections that are currently untreated or not under control.

I do not have active tuberculosis or hepatitis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive VSV-IFNβ-NIS, ipilimumab, and cemiplimab intravenously, with imaging and biopsies conducted throughout the study

Up to 2 years

Multiple visits for imaging and biopsies

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

28 days, then every 3 months for up to 1 year, then every 6 months for 1 year

Treatment Details

Interventions

• Cemiplimab
• Ipilimumab
• Recombinant Vesicular Stomatitis Virus-expressing Human Interferon Beta and Sodium-Iodide Symporter

Trial Overview The trial is testing a genetically modified virus (VSV-hIFNβ-NIS) that may target cancer cells without harming normal ones. It's used alongside ipilimumab and cemiplimab—two immunotherapy drugs—to see if they can help the immune system fight the cancer more effectively.

Participant Groups

Group I: Group E (VSV-IFNβ-NIS, ipilimumab, cemiplimab) - Peripheral T-cell lymphoma (PTCL) only Experimental Treatment 9 Interventions

PTCL patients receive VSV-IFNβ-NIS IV over 30 minutes on day 1, ipilimumab IV over 30 minutes on day -3 and cemiplimab IV over 30 minutes on day -3 in the absence of disease progression or unacceptable toxicity. Patients undergo SPECT, CT scan, PET scan throughout the study. Patients may undergo tumor biopsy, bone marrow biopsy and blood sample collection throughout the study.

Group II: Group E (VSV-IFNβ-NIS, ipilimumab, cemiplimab) - PTCL Expansion Cohort Experimental Treatment 9 Interventions

PTCL patients receive VSV-IFNβ-NIS IV over 30 minutes on day 1, ipilimumab IV over 30 minutes on day -3 and cemiplimab IV over 30 minutes on day -3 in the absence of disease progression or unacceptable toxicity. Patients undergo SPECT, CT scan, PET scan throughout the study. Patients may undergo tumor biopsy, bone marrow biopsy and blood sample collection throughout the study.

Cemiplimab is already approved in European Union, United States, Canada, Brazil for the following indications:

Approved in European Union as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)
• Non-small cell lung cancer (NSCLC)

Approved in United States as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)
• Basal cell carcinoma (BCC)
• Non-small cell lung cancer (NSCLC)

Approved in Canada as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)
• Non-small cell lung cancer (NSCLC)

Approved in Brazil as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In patients with relapsed/refractory large B cell lymphoma undergoing CAR T therapy, prolonged cytopenia (severe blood cell deficiency lasting over 30 days) is linked to increased levels of specific cytotoxic T cells that produce high amounts of interferon (IFN)-γ.

Targeting the effects of IFN-γ with treatments like thrombopoietin agonists or neutralizing antibodies may offer a new strategy to manage prolonged cytopenia associated with CAR T therapy, based on findings from single-cell RNA sequencing of bone marrow samples.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged cytopenia following CD19 CAR T cell therapy is linked with bone marrow infiltration of clonally expanded IFNγ-expressing CD8 T cells. Strati, P., Li, X., Deng, Q., et al.[2023]

In recent trials involving 32 patients with cutaneous T cell lymphoma (CTCL), recombinant human interleukin-12 (rhIL-12) demonstrated an overall response rate of nearly 50%, indicating its potential efficacy in treating this condition.

Biopsies of regressing lesions showed an increase in CD8+ and TIA-1+ T cells, suggesting that rhIL-12 may work by boosting the body's antitumor immune response, paving the way for future studies to enhance this effect with additional cytokines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role for interleukin-12 therapy of cutaneous T cell lymphoma. Rook, AH., Zaki, MH., Wysocka, M., et al.[2019]

In a phase III trial involving 144 patients with cutaneous T-cell lymphoma (CTCL), denileukin diftitox (DD) demonstrated a significant overall response rate (ORR) of 44%, compared to 15.9% for placebo, indicating its efficacy in treating this condition.

Both doses of DD (9 microg/kg/d and 18 microg/kg/d) resulted in significantly longer progression-free survival (PFS) of over 2 years, while maintaining an acceptable safety profile, with only slightly higher rates of moderately severe and severe adverse events compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma. Prince, HM., Duvic, M., Martin, A., et al.[2013]

In a phase I trial involving 10 patients with cutaneous T-cell lymphoma (CTCL), recombinant human IL-12 (rhIL-12) showed promising efficacy, with a 56% overall response rate (complete and partial responses) when administered subcutaneously, and complete tumor regression in patients receiving intralesional doses.

The treatment was generally well-tolerated, with only minor side effects reported, such as low-grade fever and headache, indicating that rhIL-12 could be a safe and effective option for enhancing antitumor immune responses in CTCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses. Rook, AH., Wood, GS., Yoo, EK., et al.[2022]

Local application of interferon (IFN) beta was highly effective in treating malignant lymphoma (ML), achieving complete response in 3 out of 4 cases, while it showed limited effectiveness in malignant melanoma (MM) with 3 cases progressing and only 1 case showing no change.

Histopathological analysis revealed significant differences between the responses in ML and MM, with ML lesions showing less inflammatory cell infiltration compared to MM, suggesting that IFN beta may offer a promising new treatment option for cutaneous ML that is resistant to traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Local application of interferon beta to skin lesions of malignant melanoma and malignant lymphoma--clinical and histopathological analysis]. Ito, Y., Jimbow, K., Miura, S., et al.[2006]

Cemiplimab (Libtayo®) is the first approved immunotherapy for patients with locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC) who cannot undergo surgery or radiotherapy, showing a clinically significant objective response rate in the phase II EMPOWER-CSCC 1 trial.

The treatment has a durable effect, with the median duration of response and overall survival not yet reached, and it has an acceptable safety profile, with manageable immune-related adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cemiplimab: A Review in Advanced Cutaneous Squamous Cell Carcinoma. Lee, A., Duggan, S., Deeks, ED.[2020]

Cemiplimab is a PD-1 monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, which is crucial for enhancing the immune response against cancer cells.

In September 2018, cemiplimab received FDA approval for treating patients with metastatic or locally advanced cutaneous squamous cell carcinoma who cannot undergo curative surgery or radiation, marking a significant advancement in cancer treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cemiplimab: First Global Approval. Markham, A., Duggan, S.[2023]

Cemiplimab demonstrated significant antitumor activity in patients with locally advanced cutaneous squamous cell carcinoma, with 44% of the 78 patients showing an objective response, including 13% achieving a complete response.

The treatment had an acceptable safety profile, with 44% of patients experiencing grade 3-4 adverse events, the most common being hypertension and pneumonia, and one treatment-related death due to aspiration pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial. Migden, MR., Khushalani, NI., Chang, ALS., et al.[2021]

Cemiplimab is the first FDA-approved treatment for patients with advanced cutaneous squamous cell carcinoma (CSCC) who cannot undergo curative surgery or radiation, demonstrating rapid and substantial antitumor efficacy in phase II clinical trials.

The treatment has an acceptable safety profile, with low rates of treatment discontinuation (7%) and death (3%), although current recommendations are based mainly on phase II data due to the lack of an approved comparator agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cemiplimab in advanced cutaneous squamous cell carcinoma. Naik, PP.[2022]

Cemiplimab-rwlc (Libtayo) is an FDA-approved immunotherapy for advanced cutaneous squamous cell carcinoma (CSCC) that works by blocking the PD-1 receptor, enhancing the immune system's ability to fight tumors.

Clinical trials have shown that cemiplimab is effective in treating CSCC, although common side effects and safety issues were noted, highlighting the need for ongoing research to improve treatment outcomes and reduce toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cemiplimab-rwlc as first and only treatment for advanced cutaneous squamous cell carcinoma. Ahmed, SR., Petersen, E., Patel, R., et al.[2019]

Biologic response modifiers like IFN-alpha and retinoids are commonly used to treat cutaneous lymphoma, showing effectiveness in both early and advanced stages, either alone or in combination with other treatments.

Novel therapies, such as anti-CD52 monoclonal antibodies, have shown promise in achieving remission for mycosis fungoides and Sezary syndrome, but their use is limited due to serious infection risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Novel treatment modalities in cutaneous T cell lymphoma. Biologic response modifiers]. Marschalkó, M.[2017]

Recombinant human interleukin-12 shows therapeutic efficacy in early-stage cutaneous T cell lymphoma, as it effectively upregulates the beta2 chain of the interleukin-12 receptor on CD8+ T cells, enhancing their anti-tumor response.

In patients with advanced Sézary syndrome and a high tumor burden, T cells fail to express the beta2 chain, indicating that interleukin-12 may be less effective in these later stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dysregulation of lymphocyte interleukin-12 receptor expression in Sézary syndrome. Zaki, MH., Shane, RB., Geng, Y., et al.[2016]

References

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

Prolonged cytopenia following CD19 CAR T cell therapy is linked with bone marrow infiltration of clonally expanded IFNγ-expressing CD8 T cells. [2023]

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

The role for interleukin-12 therapy of cutaneous T cell lymphoma. [2019]

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

Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma. [2013]

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

Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses. [2022]

5. Japan pubmed.ncbi.nlm.nih.gov

[Local application of interferon beta to skin lesions of malignant melanoma and malignant lymphoma--clinical and histopathological analysis]. [2006]

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

Cemiplimab: A Review in Advanced Cutaneous Squamous Cell Carcinoma. [2020]

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

Cemiplimab: First Global Approval. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial. [2021]

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

Cemiplimab in advanced cutaneous squamous cell carcinoma. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Cemiplimab-rwlc as first and only treatment for advanced cutaneous squamous cell carcinoma. [2019]

11. Hungary pubmed.ncbi.nlm.nih.gov

[Novel treatment modalities in cutaneous T cell lymphoma. Biologic response modifiers]. [2017]

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

Dysregulation of lymphocyte interleukin-12 receptor expression in Sézary syndrome. [2016]