Combination Immunotherapy Targeting Melanoma

Combination of CARTs, CTLs and DC Vaccines Targeting Melanoma

The purpose of this study is to assess the feasibility, safety and efficacy of combination immunotherapy based on CAR T cells, cytotoxic T lymphocytes (CTLs), and dendritic cell (DC) vaccines modified with GM-CSF and B7-2 (CD86) against melanoma, which targets CAR T specific surface antigens such as GD2, CTL specific antigens such as MAGE-A4, gp100 and a pool of melanoma specific antigens presented by the DCs. Another goal of the study is to learn more about the function and persistence of the CAR T cells and antigen-specific immune effectors in patients.

Study Overview

• Status: Recruiting
• Conditions: Melanoma
• Intervention / Treatment: Biological: Antigen-specific CAR T, CTL and DCvac to treat melanoma.

Detailed Description

Melanoma, known for having the highest mutation burden among solid tumors, has seen a steady rise in incidence over recent years. Early-stage melanoma can often be treated by surgery. As the tumor invades deeper and cancer cells metastasize, the difficulty of radical surgery increases. Although targeted therapies have significantly improved survival rates for patients with advanced melanoma, the potential for drug resistance remains a significant challenge. In this context, immunotherapy has become a new area of exploration.Therapies such as chimeric antigen receptor (CAR) T cell therapy, cytotoxic T lymphocyte (CTL) therapy, and dendritic cell vaccines have demonstrated promising clinical outcomes across various tumor types. Moreover, clinical trials exploring the application of these immunotherapies for treating melanoma are advancing steadily. Consequently, this study aims to explore a novel approach to melanoma treatment by integrating these three distinct forms of immunotherapy.

CAR T cells are a specialized type of T cells engineered to recognize and eliminate tumor cells by targeting specific surface antigens. The selection of the appropriate target antigens is crucial for the efficacy of CAR T cell therapy. Recent research has identified several promising targets for melanoma treatment, including GD2, CD70, and CSPG4. The choice of target may depend on individual patient characteristics. Among these, GD2 is expressed on the surface of a majority of melanoma cells while being minimally present in normal tissues, making it a favorable target in melanoma treatment.

CTL therapy involves stimulating effector T cells with antigen-presenting cells targeting cancer-specific antigens. In order to enhance the tumor-specific immune response, these activated antigen-presenting cells are used to generate highly specific T cells. Studies have identified several melanoma-associated antigens, such as gp100, tyrosinase, Melan-A, MAGE-A1, MAGE-A4, and NY-ESO-1. gp100 and MAGE-A4 are expressed in a significant proportion of melanoma cells and are closely linked to the development and progression of the disease. Furthermore, aberrant expression of gp100 may be implicated in the malignant transformation of melanocytes.

The dendritic cell (DC) vaccine leverages DC to activate T cells that specifically recognize target antigens, with the goal of preventing cancer recurrence and controlling tumor growth. Research has shown that DC vaccines modified with immune modulators such as GM-CSF and B7-2 (CD86) hold potential for melanoma treatment. GM-CSF plays a critical role by upregulating the expression of Bcl-xL in DC cells and reducing their sensitivity to immunosuppressive cytokines, thereby ensuring the optimal function of DCs. B7-2 serves as a vital ligand for T cell activation. By modifying DCs with B7-2, the interaction between DCs and T cells is enhanced, and promoting T cell activation, which collectively contribute to anti-tumor response.

The primary objective of this study is to evaluate the feasibility, safety, and efficacy of a combination therapy that integrates CAR T cells, CTLs, and DC vaccines modified with GM-CSF and B7-2 (CD86) for the treatment of melanoma. Additionally, the study seeks to gain further insights into the function and persistence of CAR T cells and antigen-specific immune effector s in patients.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Lung-Ji Chang, PhD; Phone Number: +86-13671121909; Email: c@szgimi.org

Study Locations

• China
  • Guangdong
    • Shenzhen, Guangdong, China, 518000
      • Recruiting
      • Shenzhen Geno-immune Medical Institute
      • Contact: Lung-Ji Chang, PhD; Phone Number: +86-13671121909; Email: c@szgimi.org
      • Contact: Lung-Ji Chang, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with melanoma have received standard first-line therapy and have been diagnosed with non-resectable, metastatic, progressive or recurrent conditions.
• The expression of melanoma specific antigens is immunohistochemically stained and verified.
• Body weight greater than or equal to 40 kg.
• Age: ≥18 year and ≤ 75 years of age at the time of enrollment.
• Life expectancy: at least 8 weeks.

• Prior Therapy:

  1. There is no limit to the number of prior treatment regimens. Any grade 3 or 4 non-hematologic toxicity of any previous therapy must be resolved to grade 2 or less.
  2. Participants must not have received hematopoietic growth factors for at least 1 week prior to mononuclear cells collection.
  3. At least 7 days must have elapsed since the completion of therapy with any biologic agent, targeted agent, tyrosine kinase inhibitor or metronomic non-myelosuppressive regimen.
  4. At least 4 weeks must have elapsed since prior therapy that includes a monoclonal antibody.
  5. At least 1 week must has elapsed since any radiation therapy at the time of study entry.
• Karnofsky/jansky score of 70% or greater.
• Cardiac function: Left ventricular ejection fraction greater than or equal to 40/55 percent.
• Pulse Ox greater than or equal to 90% on room air.
• Liver function: defined as alanine transaminase (ALT) <3x upper limit of normal (ULN), aspartate aminotransferase (AST) <3x ULN; serum bilirubin and alkaline phosphatase <2x ULN.
• Renal function: Patients must have serum creatinine less than 3 times ULN.
• Marrow function: White blood cell count ≥1000/ul, Absolute neutrophil count ≥500/ul, Absolute lymphocyte count ≥500/ul, Platelet count ≥25,000/ul (not achieved by transfusion).
• Patients with known bone marrow metastatic disease will be eligible for study as long as they meet hematologic function criteria, and the marrow disease not evaluable for hematologic toxicity.
• For all patients enrolled in this study, the patients or their legal guardians must sign an informed consent and assent.

Exclusion Criteria:

• Existing severe illness (e.g. significant cardiac, pulmonary, hepatic diseases, etc.) or major organ dysfunction, with the exception of grade 3 hematologic toxicity.
• Untreated central nervous system (CNS) metastasis: Patients with previous CNS tumor involvement that has been treated and is stable for at least 4 weeks following completion of therapy are eligible.
• Previous treatment with other genetically engineered CAR T cells.
• Active HIV, Hepatitis B virus (HBV), Hepatitis C virus (HCV) infection or uncontrolled infection.
• Patients who require systemic corticosteroid or other immunosuppressive therapy.
• Evidence of tumor potentially causing airway obstruction.
• Inability to comply with protocol requirements.
• Insufficient availability of T cells.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CAR T/CTL/DCvac cells to treat melanoma; Antigen-specific CAR T, CTL and DCvac to treat melanoma.	Biological: Antigen-specific CAR T, CTL and DCvac to treat melanoma.; Antigen-specific CAR T, CTL and DCvac to treat melanoma.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with adverse events	The toxicity profile of CAR T, CTL or DCvac is determined by Common Toxicity Criteria for Adverse Effects version 4.0	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti-tumor effects	Disease status is defined by the measurement of biochemical markers and image scan, and the outcome of treatment is classified as Complete Response/remission (CR), Very Good Partial Response/remission (VGPR), etc.	1 year
The expansion and persistency of antigen-specific CAR T cells	The investigators will monitor the expansion and functional persistency of CAR T cells in the peripheral blood of patients and examine their correlation with antitumor effects.	1 year
Immune responses after CAR T and CTL infusions and DCvac injections	IL-2 cytokine secretion profile will be assessed	1 year
Immune responses after CAR T and CTL infusions and DCvac injections	IFN-γ cytokine secretion profile will be assessed	1 year
Immune responses after CAR T and CTL infusions and DCvac injections	Anti-tumor effector activities will be assessed	1 year
Survival time of the patients	Progression free survival (PFS) of the patients treated with the CAR Ts, CTLs and DCvac will be evaluated.	3 years
Survival time of the patients	Overall survival (OS) of the patients treated with the CAR Ts, CTLs and DCvac will be evaluated.	3 years

Collaborators and Investigators

• Sponsor: Shenzhen Geno-Immune Medical Institute

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2025
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: December 9, 2024
• First Submitted That Met QC Criteria: December 12, 2024
• First Posted (Actual): December 18, 2024

Study Record Updates

• Last Update Posted (Estimated): September 9, 2025
• Last Update Submitted That Met QC Criteria: September 8, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: vaccine; melanoma; CTL; GD2; CART; chimeric antigen receptor; DC
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Skin and Connective Tissue Diseases; Melanoma
• Other Study ID Numbers: GIMI-IRB-24004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No