Two-Year INTerpath-001 Data Favor Personalized mRNA Therapy

By Sophie Lindqvist

In the phase III INTerpath-001 trial, 82.2% of patients with high-risk melanoma receiving a personalized mRNA vaccine plus immunotherapy were recurrence-free at two years, compared with 70% receiving immunotherapy alone. The international study enrolled more than 1,100 patients. At two years, 88.5% of the combination group remained free from distant metastases, versus 80.2% in the control group.

The IRCCS Foundation National Cancer Institute of Milan ranked first worldwide by enrollment volume, with 182 patients followed. The regimen was studied after surgery in patients at high risk of recurrence, not in healthy people. Dr. Roberto Patuzzo and Dr. Bianca Talione said: “It is not a preventive vaccine for healthy people. You don’t get the shot to avoid getting cancer.”

What is the personalized mRNA melanoma vaccine?

The treatment starts with a sample of the patient’s surgically removed tumor. Laboratory analysis of its DNA identifies as many as 34 neoantigens: abnormal proteins specific to that patient’s tumor. Researchers then use that information to manufacture a tailored mRNA vaccine.

The vaccine gives the immune system a molecular description of the malignant cells to recognize. Combined with immunotherapy, which releases inhibitory brakes on immune defenses, the treatment is intended to eliminate residual cancer cells that remain after surgery. It is therefore a personalized postoperative therapy, not general melanoma prevention.

How common is melanoma, and who is at risk?

Cutaneous melanoma is a malignant tumor arising from melanocytes, the epidermal cells that produce melanin to protect against ultraviolet radiation. Melanocytes also occur in the eyes and in mucosal sites, including the oropharynx and anal canal, where melanoma is much rarer in Caucasian populations.

Italy records approximately 13,000 new melanoma diagnoses each year, with an incidence of 22 cases per 100,000 people. Worldwide, melanoma ranks fifth among the most frequent tumors in both sexes. Among people younger than 50, it is the second most common tumor in males and the third in females; it can also become the first cancer diagnosed during pregnancy.

Risk reflects both environmental and genetic factors. Unprotected ultraviolet exposure, severe sunburn and tanning lamps increase risk, as do phototypes 1 and 2, a high number of moles and a family history of melanoma.

Australia’s incidence reaches 42 cases per 100,000. The experts linked that rate not only to intense sun exposure but also to a genetic predisposition amplified by more than 300 years of isolation among Northern European founder settlers. They also described a strong genetic derivation in more aggressive forms of melanoma.

Which skin changes warrant assessment?

A new mole or rapid transformation of an existing one is the most obvious warning sign. Only 40% to 50% of melanomas arise from pre-existing moles; the remaining 50% to 60% appear on previously normal skin.

Patuzzo and Talione use the ABCDE rule for self-observation:

• A: Asymmetry
• E: Irregular or jagged edges
• C: Nonuniform color
• D: Diameter greater than 6 millimeters
• E: Evolution over time

Their “ugly duckling” rule adds another trigger: a rapidly growing lesion that looks different from a person’s other moles. It may be red and need not be dark. The experts reported that 80% of patients recover permanently when melanoma is removed promptly.

How are melanoma and its spread assessed?

At a dermatoscopic clinic, a doubtful nevus that warrants histological assessment undergoes a 3 mm excisional biopsy. Initial excision margins should not exceed 3 to 5 millimeters. Patuzzo and Talione warned against immediately creating a large scar because that can alter lymphatic structures.

Once histology confirms melanoma and the tumor exceeds a certain thickness, clinicians perform lymphoscintigraphy and biopsy the sentinel lymph node. This is the first node receiving lymphatic drainage from the primary tumor and the point to which tumor cells are most likely to arrive. The result helps determine whether cells have entered the lymphatic system and provides information for staging.

Why has immunotherapy changed melanoma treatment?

Classic chemotherapy damages rapidly dividing malignant and healthy cells. Immunotherapy uses a different mechanism: it releases immune inhibitory signals, allowing lymphocytes to attack melanoma cells that have otherwise become “invisible.” The experts said this approach now allows approximately 50% of patients with advanced or metastatic disease to keep the disease under control for years.

How is the vaccine regimen given, and is it safe?

The study protocol combined intravenous immunotherapy with nine intramuscular vaccine injections, one approximately every 26 days. Total treatment lasted about one year.

The investigators reported no additional toxicity compared with immunotherapy alone. “We have not recorded any increase in toxicity compared to the use of immunotherapy alone,” they said. Vaccine-related effects resembled ordinary vaccination reactions: fatigue, fever and pain at the injection site.

What does this change for clinicians?

At present, it changes practice mainly by defining an investigational workflow rather than a standard treatment. Production occurs in the United States, and the Milan institute identified production times and costs as the immediate logistical and economic constraints. Possible European production may be necessary to make the therapy sustainable.

The larger research program also includes applying similar vaccines to cancers without current cures, including pancreatic and lung cancer. The institute is investing in surgical de-escalation, using less destructive operations, and in liquid biopsy, which seeks to identify diseased cells through a blood test.

Before the vaccine can become approved and routinely available in hospitals, further trials, definitive five-year overall-survival data and regulatory processes involving the European Medicines Agency and Italy’s AIFA remain necessary. The next decisive test is whether the two-year benefit persists in those survival data and regulatory review.