Phase 1 Study Using TRIMELVax for Stage IIIC / IV Melanoma Patients

A new cancer vaccine called TRIMELVax will be tested as a potential treatment for patients with unresectable stage III or stage IV melanoma who have progressed to anti-PD1 immune checkpoint blockers treatment or who have presented unacceptable toxicity to the treatment. This vaccine breaks the body's tolerance to cancer cells and triggers a specific immune response against tumors. It is made from heat-treated melanoma tumor cells combined with a natural booster. In tests with mice, the vaccine caused tumor shrinkage and activated a strong immune response against melanoma and colorectal cancer.

TRIMELVax consists of three types of human melanoma-destroyed cells that are heat-treated and mixed with a booster derived from a mollusk hemocyanin. Patients will receive four injections of the vaccine in one treatment cycle.

A Phase I clinical trial will be conducted to test the safety of TRIMELVax for stage IIIC and IV melanoma patients with unresectable stage III or stage IV melanoma who have progressed to anti-PD1 immune checkpoint blockers treatment or who have presented unacceptable toxicity to the treatment. The study includes 20 patients meeting specific criteria, such as being over 18 years old, having confirmed stage IIIC or IV melanoma, and having a good performance status.

The study's main goals are to assess potential side effects and measure the vaccine's impact on the patient's immune system. Blood samples will be taken before each treatment and monthly for the first year of follow-up. We will look for specific markers on certain immune cells to evaluate the vaccine's effectiveness. We will also conduct a test to evaluate the immune response one month after the last vaccine dose.

The study is conducted in two Chilean medical centers, the Oncology Service at the Hospital Salvador, where patients receive their standard cancer treatment and support. Our primary focus is ensuring the vaccine's safety and understanding its impact on the immune system.

Cancer vaccines emerge as a promising treatment alternative for patients refractory to immune checkpoint blockers (ICBs) because vaccination can break the tolerance, generating new specific immune responses capable of modulating the tumor microenvironment. TRIMELVax is a new immunogenic formulation prototype developed for treating solid tumors. It is obtained from heat-conditioned melanoma tumor cell lysates combined with a natural adjuvant. Preclinical studies showed tumor regression in murine models challenged with melanoma and colorectal cancer, activating a robust immune response against these tumors. The present vaccine is based on three allogeneic melanoma cell lysates pre-activated by a heat shock, which includes the direct subcutaneous injection as a vaccine, combined with an adjuvant derived from a mollusk hemocyanin, in one cycle of four injections. The present phase I clinical study entitled "Phase 1 Clinical Trial to Determine the Safety of TRIMELVax for Stage IIIC and IV Melanoma Patients, in Progression to Immunotherapy Treatment (Checkpoint Inhibitors)" will include 20 stage IV melanoma patients according to the following inclusion criteria: People over 18 years old with histological confirmation of AJCC malignant melanoma Stage IIIC or IV. Performance Status 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale. Life expectancy over 3 months. Disease progression after anti-PD1 immune checkpoint blockers treatment or who have presented unacceptable toxicity to the treatment. Patients will be recruited in the Hospital del Salvador Oncology Service, where they will receive their experimental treatment and standard cancer care support.

Primary Objectives: Possible adverse effects should be evaluated to ensure the safety of the treatment and follow the CTCAE criteria (Common Terminology Criteria for Adverse Events) version 5.0. Due to the many adverse events that will be monitored, the CTCAE criteria are listed at the end of the trial protocol.

To evaluate the induction of a specific systemic immune response, peripheral blood will be drawn from the patients before each treatment administration and monthly during the first year of follow-up. Different surface and intracellular markers will be measured on CD8+ and CD4+ T lymphocytes. This group of markers was named the "rescue score," and it follows the proposal of Huang et al. (2017) and Sarhan et al. (2017) to evaluate immune responses to immunotherapies in humans. In addition, the Delayed Hypersensitivity or DTH test will be used thirty days after the last immunization to evaluate the in vivo immune response as described in López et al. (2009).

Eligibility Criteria:
Inclusion Criteria:

* People over 18 years old
* Histological confirmation of AJCC malignant melanoma Stage IIIC or IV.
* Performance Status 0 or 1 in the scale of Eastern Cooperative Oncology Group (ECOG).
* Life expectancy over 3 months
* Prior to the beginning of the study, participants should be aware of the risk information and express their willingness to participate by a written consent.
* Disease progression after the use of checkpoint inhibitors immunotherapy.

Exclusion Criteria:

* History of other cancers diagnosed in a period of less than 5 years, except for squamous or basal cell skin cancer, cervical cancer in situ or superficial bladder cancer, properly treated and cured.
* Ocular melanoma.
* Old or recent story of autoimmune disease.
* Systemic use of corticosteroids or immunosuppressants within 28 days prior to the start of the study. The use of inhalation corticosteroids is allowed.
* Adrenal insufficiency, requiring the use of corticosteroids, at any dose.
* Presence of symptomatic cardiac arrythmias, atrial fibrillation or prolongation of the QT-interval.
* Arterial hypertension that is not under control (systolic pressure higher than 160 mmHg and or diastolic pressure higher than 100 mmHg.
* History of symptomatic cardiovascular diseases over the last 12 months (unstable coronary disease, symptomatic vascular disease, heart failure/ functional capacity III or IV according to the New York Heart Association, history of cerebrovascular accident including transient ischemic attack, untreated deep vein thrombosis, pulmonary embolism).
* History of HIV, HBV and / or HCV infections
* Major surgery over the last 28 days
* History of splenectomy
* Uncontrolled infection or any known medical condition, that according to the investigator's interpretation may increase the risk involved in the participation of the study, or interfere with treatment or follow ups, or interfere with the interpretation of safety results.
* Inability to carry out the informed consent process.
* History of allogeneic bone marrow transplant.
* Ongoing pregnancy or breastfeeding