Immunotherapy drug shows promise against aggressive cancers

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An enhanced version of an immunotherapy drug has shown significant promise against aggressive cancers in phase-1 trials, according to researchers.

While CD40 agonist antibodies -- a class of cancer drugs -- have, over the past 20 years, been effective at activating the immune system to kill cancer cells in animal models, they have also caused dangerous systemic inflammatory responses, low platelet counts, and liver toxicity, among other adverse reactions -- even at a low dose in humans.

However, in 2018, a team of US researchers led by the Rockefeller University enhanced the CD40 agonist antibody to improve its efficacy and limit its serious side effects.

The results from the Phase I clinical trial of the drug -- dubbed 2141-V11 -- showed that of the 12 patients, six patients saw their tumours shrink, including two that saw them disappear completely.

"Seeing these significant shrinkages and even complete remission in such a small subset of patients is quite remarkable," said first author Juan Osorio, a medical oncologist at Memorial Sloan Kettering Cancer Center.

Notably, the effect wasn't limited to tumours that were injected with the drug; tumours elsewhere in the body either got smaller or were destroyed by immune cells, revealed the findings published in the journal Cancer Cell.

"This effect -- where you inject locally but see a systemic response - that's not something seen very often in any clinical treatment," said Jeffrey V. Ravetch, from Rockefeller, who led the study. "It's another very dramatic and unexpected result from our trial."

CD40 is a cell surface receptor and member of the tumour necrosis factor (TNF) receptor superfamily, proteins that are largely expressed by immune cells.

When triggered, CD40 prompts the rest of the immune system to spring into action, promoting antitumour immunity and developing tumour-specific T cell responses.

In 2018, Ravetch's lab engineered 2141-V11, a CD40 antibody that binds tightly to human CD40 receptors and is modified to enhance its crosslinking by also engaging a specific Fc receptor.

It proved to be 10 times more powerful in its capacity to elicit an antitumor immune response.

From being administered intravenously, the team injected the drug directly into tumours.

Of those 12 patients with melanoma, renal cell carcinoma, and different types of breast cancer, none suffered the serious side effects seen with other CD40 drugs.

Six experienced systemic tumour reduction, two patients with melanoma and breast cancer -- both notoriously aggressive and recurring -- experienced complete remission.

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