Clinical trial NCT06152367: Immunization With Autologous Dendritic Cells and Tumor Lysates in Melanoma Patients
Official title: Phase I/II Trial In Stage III/IV Malignant Melanoma Using Autologous Dendritic Cells Loaded With Tumor Cell Lysates And Low Doses Of Proleukin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Stage III Malignant Melanoma of Skin AJCC V6
Stage IV Malignant Melanoma of Skin
Lead sponsor: University of Chile
Sponsor class: OTHER
First posted: 2023-11-30
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Implementing this protocol has its ethical justification in that patients with metastatic melanoma, once tumor invasion has reached beyond the lymph node barrier, cannot possibly be treated satisfactorily with traditional surgery methods, radiotherapy, or conventional available chemotherapy. The disseminated tumor is refractory to all standard treatments. Almost 100% of patients who develop distant metastases will die from their disease, either from complications or cachexia. Therefore, immunotherapy based on immunological stimulation with immunocompetent dendritic cells, added to immunological reinforcement with IL-2, can, according to the evidence emanating from ongoing clinical protocols, produce a prolongation of survival with better quality and, in some cases, with partial or total regression of the tumor.

General objective: It is to study the clinical and immunological response of patients treated with vaccines based on autologous dendritic cells loaded with tumor antigens, derived from allogeneic melanoma extracts, in combination or not, with intercalated low doses of recombinant human interleukin 2 (rhIL2) PROLEUKIN ® (aldesleukin). MAIN SPECIFIC OBJECTIVE: - SAFETY: Safety in administering dendritic cell preparation; local and systemic toxicity estimation. Determination of adverse reactions such as fever, nausea, allergy, neurological and cardiovascular symptoms. Local toxicity in the administration area. - MEASUREMENT OF THE IMMUNE RESPONSE: Based on in vivo and in vitro parameters: - In vivo response: Measure the type IV Delayed Hypersensitivity (DTH) response. It consists of a crossover test in which the response is compared to tissue interaction in vivo between dendritic cells sensitized with tumor extracts and their respective control unloaded dendritic cells. - In vitro response: ELISPOT assays, measurement of IFN-γ gamma production in peripheral blood of treated patients. Compare the specific immune response after each cycle of therapy through measurement of IFN-γ production by tumor-specific CTL. Cytotoxic radioactive chromium release assays to measure anti-tumor response mediated by CTL and NK. ELISA assays for quantifying cytokines (IFN-γ, IL-10) in patient serum after each cycle of therapy.

Detailed description: Vaccination of Melanoma Patients Using DCs Loaded with Allogeneic Melanoma Extracts.

In Chile, this study constitutes the first phase I clinical trial for treating advanced malignant melanoma using dendritic cell vaccines loaded with allogeneic tumor extracts complemented or not with low doses of rIL-2. Since chemotherapy and radiotherapy only offer palliative effects in advanced melanoma, resulting in an inferior prognosis for these patients, the trial intends to develop a protocol that would adapt to the reality of Chile, allowing for a combination of high technology and low costs.

After obtaining approval from the human research ethics committee from Universidad de Chile, 86 patients will be recruited who will be duly informed about the scope of these protocols and the realistic prospects of success. The participants then will undergo a comprehensive health check to assess their overall health. The participants will undergo a leukapheresis at the blood bank of the Clinical Hospital of the University de Chile. Peripheral blood mononuclear cells (PBMCs) will be separated using a Ficoll-Hypaque gradient in the laboratory of Antitumor Immunology at the Institute of Biomedical Sciences, Faculty of Medicine of the University de Chile. Some of the cells will be cryopreserved in liquid nitrogen for future use. Approximately 1.8x108 PBMCs will be placed in 6-well culture plates and incubated at 37°C and 7% CO2 for two hours. The suspended cells, peripheral blood lymphocytes (PBLs), will be removed and frozen for later use. The monocytes adhering to the plastic will be incubated for seven days in a serum-free culture medium (AIM-V therapeutic, GIBCO, BRL) in the presence of 500 U/ml of IL-4 and 800 U/ml of GM-CSF. On the sixth day, the DCs will be pulsed with tumor extracts from allogeneic melanoma cell lines, previously checked for sterility, and incubated for 6 hours at 37°C and 7% CO2, followed by maturation stimulus with TNF-alpha for 12 to 18 hours. Mature DCs will be characterized by flow cytometry. Approximately 10 to 20 x 106 pulsed DCs will be subcutaneously injected. This routine will be repeated weekly for at least four times and a maximum of 6 times. After the fourth dose, the participant's general condition, possible clinical regressions, adverse side effects, and the effects of the treatment on the immune system will be evaluated. This evaluation will be done through in vivo delayed-type hypersensitivity (DTH) assays using melanoma extracts and their respective controls. Planned in vitro assays for immune response measuring will include the detection of anti-melanoma CTL precursors by ELISPOT, cytokine production, proliferation assays, and quantifying the CD4/CD8 ratio by flow cytometry.

Eligibility criteria: Inclusion Criteria:

* Patients with histologically confirmed melanoma of the skin: Breslow, Clark, histological type. Location of the primary, clinical, or pathological regional status.
* Complete staging demonstrating the presence of distant metastases, either visceral or in soft tissues or bone tissue: Brain, Lung, Abdomen, and Pelvis CT and bone scintigraphy.
* Objectively measurable disease by clinical or radiological means
* Karnofsky's Performance Status is more significant than 70%
* Life expectancy greater than three months
* Patients over 18 years old
* Informed consent from the patient to participate in the protocol

Exclusion Criteria:

* Age greater than or equal to 65 years
* Ongoing active infections, including viral immunodeficiency
* Previous chemotherapy within less than two months
* Concomitant malignant tumors (e.g., Chronic Lymphocytic Leukemia, etc.)
* Uncontrolled concomitant diseases (Hypertension, unstable Diabetes mellitus, renal diseases requiring dialysis)
* Situations or conditions requiring urgent surgical intervention, such as intestinal obstruction due to metastasis
* Pregnancy or lactation
* Concurrent participation in other therapeutic research protocols
* Any condition that compromises the objectives of this study.

Removal Criteria from the Study:

* By the patient's decision to discontinue the study.
* Intolerable adverse reactions, according to WHO Criteria Grading Toxicities
* Intercurrent illness that may compromise the patient's life or interfere with the treatment study evaluation
* Requirements for concomitant medication that may interfere with study results.
* Failure to complete the study entirely
* Failure to follow up on the patient.

Primary outcomes:
measure: Incidence of treatment-emergent adverse events [safety and tolerability]
timeFrame: Every four weeks the first year after treatment. Every two months during the second year after treatment.
measure: Local immune response measurement by DTH
timeFrame: Every four weeks the first year after treatment. Every two months during the second year after treatment.
measure: Systemic immune response measurement in PBMC
timeFrame: Every four weeks the first year after treatment. Every two months during the second year after treatment.
measure: Systemic IFN-γ response measurement in serum
timeFrame: Every four weeks the first year after treatment. Every two months during the second year after treatment.
measure: Systemic IL-17 response measurement in serum
timeFrame: Every four weeks the first year after treatment. Every two months during the second year after treatment.
measure: Systemic TGF-b response measurement in serum
timeFrame: Every four weeks the first year after treatment. Every two months during the second year after treatment.
measure: Systemic IL-10 response measurement in serum
timeFrame: Every four weeks the first year after treatment. Every two months during the second year after treatment.
measure: Systemic TNF-a response measurement in serum
timeFrame: Every four weeks the first year after treatment. Every two months during the second year after treatment.
measure: Systemic cytotoxic T cell-mediated tumor-specific IFN-g release
timeFrame: Every four weeks the first year after treatment. Every two months during the second year after treatment.
measure: Systemic cytotoxic T cell-mediated anti-tumor cell cytotoxicity
timeFrame: Every four weeks the first year after treatment. Every two months during the second year after treatment.
Secondary outcomes:
measure: Overall survival
timeFrame: Every four weeks the first year after treatment. Every two months during the second year after treatment.
measure: Progression-free survival
timeFrame: Every four weeks the first year after treatment. Every two months during the second year after treatment.
measure: Clinical response measurement
timeFrame: Every four weeks the first year after treatment. Every two months during the second year after treatment.
measure: Global health status scores measurement
timeFrame: Evaluated at immunization 1 (day 0; baseline level), 3 (day 20) and 4 (day 50), and also at DTH test (day 80)
measure: Physical functioning scale scores measurement
timeFrame: Evaluated at immunization 1 (day 0; baseline level), 3 (day 20) and 4 (day 50), and also at DTH test (day 80)
measure: Pain symptom scale scores measurement
timeFrame: Evaluated at immunization 1 (day 0; baseline level), 3 (day 20) and 4 (day 50), and also at DTH test (day 80)
measure: Performance status response
timeFrame: Every four weeks the first year after treatment. Every two months during the second year after treatment.
Other outcomes:
Locations:
city: Santiago
country: Chile
facility: Faculty of Medicine, University of Chile
state: RM
Study officials:
affiliation: FACULTY OF MEDICINE, Universidad de Chile
name: Flavio Salazar-Onfray, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Aguilera R, Saffie C, Tittarelli A, Gonzalez FE, Ramirez M, Reyes D, Pereda C, Hevia D, Garcia T, Salazar L, Ferreira A, Hermoso M, Mendoza-Naranjo A, Ferrada C, Garrido P, Lopez MN, Salazar-Onfray F. Heat-shock induction of tumor-derived danger signals mediates rapid monocyte differentiation into clinically effective dendritic cells. Clin Cancer Res. 2011 Apr 15;17(8):2474-83. doi: 10.1158/1078-0432.CCR-10-2384. Epub 2011 Feb 3.
citation: Duran-Aniotz C, Segal G, Salazar L, Pereda C, Falcon C, Tempio F, Aguilera R, Gonzalez R, Perez C, Tittarelli A, Catalan D, Nervi B, Larrondo M, Salazar-Onfray F, Lopez MN. The immunological response and post-treatment survival of DC-vaccinated melanoma patients are associated with increased Th1/Th17 and reduced Th3 cytokine responses. Cancer Immunol Immunother. 2013 Apr;62(4):761-72. doi: 10.1007/s00262-012-1377-3. Epub 2012 Dec 15.
citation: Tittarelli A, Gonzalez FE, Pereda C, Mora G, Munoz L, Saffie C, Garcia T, Diaz D, Falcon C, Hermoso M, Lopez MN, Salazar-Onfray F. Toll-like receptor 4 gene polymorphism influences dendritic cell in vitro function and clinical outcomes in vaccinated melanoma patients. Cancer Immunol Immunother. 2012 Nov;61(11):2067-77. doi: 10.1007/s00262-012-1268-7. Epub 2012 May 3.
citation: Garcia-Salum T, Villablanca A, Matthaus F, Tittarelli A, Baeza M, Pereda C, Gleisner MA, Gonzalez FE, Lopez MN, Hoheisel JD, Norgauer J, Gebicke-Haerter PJ, Salazar-Onfray F. Molecular signatures associated with tumor-specific immune response in melanoma patients treated with dendritic cell-based immunotherapy. Oncotarget. 2018 Mar 30;9(24):17014-17027. doi: 10.18632/oncotarget.24795. eCollection 2018 Mar 30.
citation: Lopez MN, Pereda C, Segal G, Munoz L, Aguilera R, Gonzalez FE, Escobar A, Ginesta A, Reyes D, Gonzalez R, Mendoza-Naranjo A, Larrondo M, Compan A, Ferrada C, Salazar-Onfray F. Prolonged survival of dendritic cell-vaccinated melanoma patients correlates with tumor-specific delayed type IV hypersensitivity response and reduction of tumor growth factor beta-expressing T cells. J Clin Oncol. 2009 Feb 20;27(6):945-52. doi: 10.1200/JCO.2008.18.0794. Epub 2009 Jan 12.