Modified Virus and Immunotherapy for T-Cell Lymphoma
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Mayo Clinic
Must not be taking: Chemotherapy, Immunotherapy, Experimental agents
Disqualifiers: Active infection, Hepatitis, Cardiac disease, others
No Placebo Group
Breakthrough Therapy
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.12345
Is cemiplimab generally safe for humans?
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.2341112
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)
See 15 more
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.
See 7 more
Trial 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 (Monoclonal Antibodies)
- Ipilimumab (Checkpoint Inhibitor)
- Recombinant Vesicular Stomatitis Virus-expressing Human Interferon Beta and Sodium-Iodide Symporter (Virus Therapy)
Trial OverviewThe 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
2Treatment groups
Experimental Treatment
Group I: Group E (VSV-IFNβ-NIS, ipilimumab, cemiplimab) - Peripheral T-cell lymphoma (PTCL) onlyExperimental Treatment9 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 CohortExperimental Treatment9 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)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Mayo Clinic in ArizonaScottsdale, AZ
Mayo Clinic in RochesterRochester, MN
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Who Is Running the Clinical Trial?
Mayo ClinicLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Prolonged cytopenia following CD19 CAR T cell therapy is linked with bone marrow infiltration of clonally expanded IFNγ-expressing CD8 T cells. [2023]Autologous anti-CD19 chimeric antigen receptor T cell (CAR T) therapy is highly effective in relapsed/refractory large B cell lymphoma (rrLBCL) but is associated with toxicities that delay recovery. While the biological mechanisms of cytokine release syndrome and neurotoxicity have been investigated, the pathophysiology is poorly understood for prolonged cytopenia, defined as grade ≥3 cytopenia lasting beyond 30 days after CAR T infusion. We performed single-cell RNA sequencing of bone marrow samples from healthy donors and rrLBCL patients with or without prolonged cytopenia and identified significantly increased frequencies of clonally expanded CX3CR1hi cytotoxic T cells, expressing high interferon (IFN)-γ and cytokine signaling gene sets, associated with prolonged cytopenia. In line with this, we found that hematopoietic stem cells from these patients expressed IFN-γ response signatures. IFN-γ deregulates hematopoietic stem cell self-renewal and differentiation and can be targeted with thrombopoietin agonists or IFN-γ-neutralizing antibodies, highlighting a potential mechanism-based approach for the treatment of CAR T-associated prolonged cytopenia.
The role for interleukin-12 therapy of cutaneous T cell lymphoma. [2019]Recent phase I and phase II trials using recombinant human interleukin-12 (rhIL-12) for cutaneous T cell lymphoma (CTCL) have been completed. Observations on 32 evaluable patients revealed an overall response rate approaching 50 percent. Biopsy of regressing lesions revealed an increase in numbers of CD8+ and/or TIA-1+ T cells. These results suggest that rhIL-12 may induce lesion regression by augmenting antitumor cytotoxic T cell responses. Future trials will be focused on strategies for further immune enhancement by the concomitant use of additional immune augmenting cytokines with rhIL-12.
Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma. [2013]PURPOSE This phase III, placebo-controlled, randomized trial was designed to investigate efficacy and safety of two doses of denileukin diftitox (DD; DAB(389)-interleukin-2 [IL-2]), a recombinant fusion protein targeting IL-2 receptor-expressing malignant T lymphocytes, in patients with stage IA to III, CD25 assay-positive cutaneous T-cell lymphoma (CTCL), including the mycosis fungoides and Sézary syndrome forms of the disease, who had received up to three prior therapies. The primary end point was overall response rate (ORR). PATIENTS AND METHODS Patients (N = 144) with biopsy-confirmed, CD25 assay-positive CTCL were randomly assigned to DD 9 microg/kg/d (n = 45), DD 18 microg/kg/d (n = 55), or placebo infusions (n = 44), administered for 5 consecutive days every 3 weeks for up to eight cycles. Patients were monitored for drug efficacy, clinical benefit, and safety of DD. RESULTS ORR was 44% for all participants treated with DD (n = 100; 10% complete response [CR] and 34% partial response [PR]) compared with 15.9% for placebo-treated patients (2% CR and 13.6% PR). ORR was higher in the 18 microg/kg/d group versus the 9 microg/kg/d group (49.1% v 37.8%, respectively), and both doses were significantly superior to placebo. Progression-free survival (PFS) was significantly longer (median, > 2 years) for both DD doses compared with placebo (median, 124 days; P
Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses. [2022]Progression of cutaneous T-cell lymphoma (CTCL) is associated with profound defects in cell-mediated immunity and depressed production of cytokines, which support cell-mediated immunity. Because we have observed marked defects in interleukin-12 (IL-12) production in CTCL and because IL-12 is critical for antitumor cytotoxic T-cell responses, we initiated a phase I dose escalation trial with recombinant human IL-12 (rhIL-12) where patients received either 50, 100, or 300 ng/kg rhIL-12 twice weekly subcutaneously or intralesionally for up to 24 weeks. Ten patients were entered: 5 with extensive plaque, 3 with Sezary syndrome, and 2 with extensive tumors with large cell transformation. One patient with Sezary syndrome dropped out after 1 week for personal reasons. Subcutaneous dosing resulted in complete responses (CR) in 2 of 5 plaque and partial responses (PR) in 2 of 5 plaque, and 1 of 2 Sezary syndrome (overall response rate CR+PR 5 of 9, 56%). A minor response also occurred in 1 of 5 plaque patients. Intralesional dosing resulted in individual tumor regression in 2 of 2 patients. Biopsy of regressing lesions showed a significant decrease in the density of the infiltrate in all cases and complete resolution of the infiltrate among those with clinical lesion resolution. An increase in numbers of CD8-positive and/or TIA-1-positive T cells were observed on immunohistochemical analysis of skin biopsy specimens obtained from regressing skin lesions. Adverse effects of rhIL-12 on this regimen were minor and limited and included low-grade fever and headache. One patient discontinued rhIL-12 at week 6 because of depression. These results suggest that rhIL-12 may augment antitumor cytotoxic T-cell responses and may represent a potent and well-tolerated therapeutic agent for CTCL.
[Local application of interferon beta to skin lesions of malignant melanoma and malignant lymphoma--clinical and histopathological analysis]. [2006]Interferon (IFN) beta was applied locally to skin lesions of malignant melanoma (MM: 3 cases in stage IV and 1 case in stage II) and malignant lymphoma (ML: 3 cases of mycosis fungoides in stages II-III and 1 case of primary cutaneous lymphoma in stage III). It was found that IFN beta was remarkably effective for ML (3 in CR and 1 in PR), but far less effective for MM (3 in PD and 1 in NC). Biopsy specimens of clinically regressed areas revealed histopathology entirely different from each other, skin lesion of MM being infiltrated by numerous inflammatory cells such as lymphocytes and macrophages, whereas that of ML infiltrated Least. Local application of IFN beta appears to provide a new modality for treatment of cutaneous ML, which has the primary lesions on skin and has been hardly controlled by systemic chemoimmunotherapy.
Cemiplimab: A Review in Advanced Cutaneous Squamous Cell Carcinoma. [2020]Cemiplimab (Libtayo®) is an antibody immunotherapy that stimulates an anti-cancer response via programmed cell death protein-1 (PD-1) blockade. It is the first approved treatment in the USA and EU for patients with locally advanced (laCSCC) or metastatic (mCSCC) cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiotherapy. Approval was based largely on positive results from the phase II EMPOWER-CSCC 1 trial in this patient population. In this pivotal trial, treatment with intravenous cemiplimab 3 mg/kg once every 2 weeks or 350 mg once every 3 weeks resulted in a clinically significant objective response rate across laCSCC and mCSCC patient groups. Furthermore, responses appear to be durable, as the median duration of response has not yet been reached. Similarly, the median overall survival has also not yet been reached as of the latest data cut-off date. The safety and tolerability profile of cemiplimab was acceptable, with most immune-related adverse events being clinically manageable with appropriate therapy or discontinuation of cemiplimab. Overall, cemiplimab has a durable, clinically significant effect and an acceptable tolerability and safety profile. As the first approved treatment for this indication, cemiplimab represents a welcome therapeutic advance for patients with advanced CSCC.
Cemiplimab: First Global Approval. [2023]Cemiplimab (LIBTAYO®; cemiplimab-rwlc), a human programmed death receptor-1 (PD-1) monoclonal antibody that binds to PD-1 and blocks its interaction with programmed death ligands 1 (PD-L1) and 2 (PD-L2), is being developed by Regeneron Pharmaceuticals and Sanofi Genzyme. The drug is being investigated as a treatment for various cancers and in September 2018 received approval in the USA for the treatment of patients with metastatic cutaneous squamous cell carcinoma or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation. This article summarizes the milestones in the development of cemiplimab leading to this first global approval for the treatment of advanced cutaneous squamous cell carcinoma.
Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial. [2021]Cemiplimab has shown substantial antitumour activity in patients with metastatic cutaneous squamous cell carcinoma. Patients with locally advanced cutaneous squamous cell carcinoma have poor prognosis with conventional systemic therapy. We present a primary analysis of the safety and antitumour activity of cemiplimab in patients with locally advanced cutaneous squamous cell carcinoma.
Cemiplimab in advanced cutaneous squamous cell carcinoma. [2022]Cemiplimab, a high-affinity, highly potent human monoclonal antibody that binds to the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) receptor, is the only drug to attain Food and Drug Administration (FDA) approval and marketing authorization from the European Commission for use in patients with metastatic and locally advanced cutaneous squamous cell carcinoma (CSCC) who are not candidates for curative surgery or curative radiation therapy as a first- or later-line treatment. In pivotal phase II clinical testing, cemiplimab showed rapid and substantial antitumor efficacy and acceptable safety. This systematic review was aimed at evaluating the efficacy and safety of cemiplimab in patients with advanced CSCC. To this end, I reviewed EMBASE, MEDLINE, PubMed, and clinical trial registries/databases by using the following keywords alone or in combination: "cemiplimab," "Libtayo," "cutaneous squamous cell carcinoma," "REGN2810," and "SER439684." Cemiplimab showed clinical efficacy and considerable safety and was associated with low rates of treatment discontinuation (7%) and death (3%). However, the current recommendation is primarily based on only phase II clinical testing due to the absence of an approved comparator agent.
Cemiplimab-rwlc as first and only treatment for advanced cutaneous squamous cell carcinoma. [2019]Introduction: In September of 2018, the United States Federal Drug Administration (FDA) approved cemiplimab-rwlc (Libtayo) for advanced cutaneous squamous cell carcinoma (CSCC). Cemiplimab is an intravenous human monoclonal antibody directed against programmed cell death-1 receptor (PD-1). Cemiplimab blocks T-cell inactivation and enhances the immune system's anti-tumor response. Areas Covered: We review CSCC and the studies leading to cemiplimab's approval, including common side effects and safety issues experienced during the clinical trials. Expert Opinion: Immunotherapy, specifically checkpoint inhibitors, represents an increasingly utilized class of medications that is proving to be an effective treatment option for those with certain cancers. Over time, immunotherapy is likely to be the standard of care for immune-sensitive tumors. There are many challenges that the field faces, including the identification of reliable biomarkers to better predict response, decreasing toxicity, and the potential treatment of organ transplant patients.
[Novel treatment modalities in cutaneous T cell lymphoma. Biologic response modifiers]. [2017]Biologic response modifiers. Biologic response modifiers such as IFN-alpha, retinoids and extracorporeal photopheresis have been widely used in the treatment of cutaneous lymphoma. The novel treatment modalities like cytokine therapies, monoclonal antibodies and fusion proteins have been used only in limited number of patients with therapy refractory diseases, in advanced stages. The treatment responses of novel cytokine therapies, IFN-gamma, IL-2 and IL-12, are encouraging. Anti- CD52 monoclonal antibody treatment resulted in complete or partial remission in both mycosis fungoides and Sezary syndrome, however serious infectious complications hinder the wide-range usage. DAB 389IL-2 fusion protein-consisting of the toxic portion of diphtheria toxin and the IL-2 sequence has been used for advanced stages of CTCL. RXR retinoids are effective treatment for both early and advanced stages, in form of monotherapy or in combination treatment.
Dysregulation of lymphocyte interleukin-12 receptor expression in Sézary syndrome. [2016]Initial phase I and II clinical trials with recombinant human interleukin-12 have demonstrated the therapeutic efficacy of this cytokine in early stage cutaneous T cell lymphoma as compared with more advanced stages such as the leukemic Sézary syndrome. In an effort to optimize the use of recombinant human interleukin-12, using flow cytometry we studied the regulation of the interleukin-12 receptor beta1 (high affinity chain) and beta2 (chain necessary for interleukin-12 signal transduction) on normal volunteer CD4+ and CD8+ T cells and CD4+ and CD8+ cells from eight patients with different degrees of leukemic involvement with Sézary syndrome. The beta1 chain was not readily detectable on resting normal and T cells from Sézary patients, but expression was induced following T cell activation with phytohemagglutinin. Similarly, the beta2 chain was not detectable on resting normal volunteer T cells, but could be induced following phytohemagglutinin stimulation. Moreover, the beta2 chain on normal volunteer T cells was markedly upregulated following short-term culture with interferon-gamma or recombinant human interleukin-12. CD8+ T cells routinely exhibited a greater expression of beta2 than did CD4+ T cells. In marked contrast, both CD4+ and CD8+ T cells from patients with Sézary syndrome and a high tumor cell burden (> 50% circulating atypical Sézary T cells) failed to express the beta2 chain under any culture conditions. Although, culture with anti-interleukin-10 also markedly increased beta2 expression on normal volunteer T cells, this failed to induce expression on either CD4+ or CD8+ T cells from Sézary patients and a high tumor burden. Investigation of patients with Sézary syndrome and a low tumor cell burden (