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Targeted Immunotherapy Shown to Shrink, Stop Tumors

T-cells and cancer cells

Killer T-cells surround a cancer cell (NICHD, Flickr)

12 Nov. 2021. Results from tests with lab mice show an experimental targeted cancer therapy invoking the immune system shrinks tumors and prevents their recurrence. Findings from the study are scheduled for presentation today by researchers from biotechnology company Asher Biotherapeutics at the Society for Immunotherapy of Cancer or SITC annual meeting in Washington, D.C.

Asher Bio in South San Francisco designs immunotherapies that address a continuing problem from pleiotropy, a condition where changes in a single gene can affect multiple human traits. In cancer immunotherapies, pleiotropy can cause unintended changes in cells and tissue other than the tumors, when the treatment’s cancer targets are attacked. Asher Bio’s technology, called cis-targeting, addresses receptor proteins at two sites on surfaces of a single immune system cell, the therapeutic antigen target and a separate receptor that simulates immune responses, called an immunomodulator.

The company says it applies computational techniques to screen immune system cells and sub-types for therapeutic benefits, but also for possible unintended toxicities or reverse effects that block the therapy. Asher Bio then engineers selected immune system cells to produce cytokine enzymes that bind only on specific tumor targets and boost their potency.

Asher Bio’s lead product, code-named AB248, is an engineered protein that addresses receptor pathways for cancer-killing CD8+ T-cells in the immune system for interleukin-2 or IL-2 cytokines. Various IL-2 forms are already approved for treating some metastatic solid tumor cancers, but because of pleiotropy, IL-2 can also stimulate other unintended immune system cell types. And, because of its short active lifetime, IL-2 is needed in high doses, which can be toxic, causing heart and blood damage.

Tumor rejections and complete responses

In an oral presentation at the SITC meeting, a team led by Asher Bio’s scientific founder Robert Schreiber, an immunologist at Washington University in St. Louis, reported on tests of CD8-IL2, an AB248 surrogate, in lab mice induced with advanced sarcoma, or soft-tissue cancer. The results show one dose of CD8-IL2 causes rejection of tumors in 90 percent of recipient mice, defined as complete regression of tumors and without recurrence.

Mice receiving CD8-IL2 also show increased production of T-cells activated and targeted to attack the tumors. Plus, say the researchers, a similar set of cancer-induced mice show little, if any, response to high doses of IL-2 cytokines alone. In addition, mice receiving CD8-IL2 do not show weight loss, an indicator of tolerating the treatment.

A separate poster presentation at SITC offers results from another preclinical test, by a team led by Asher Bio’s AB248 program chief Kelly Moynihan. Those findings show a majority of lab mice induced with colorectal cancer have a complete response — where no cancer is detected — to a single CD8-IL2 treatment, more responses than a form of IL-2 cytokine alone given to similar cancer-induced mice.

And say the authors, a combination of CD8-IL2 and anti-PD1 checkpoint inhibitor treatments result in complete responses for all mice induced with melanoma. Moreover, CD8-IL2 treatments invoke a selective expansion of CD8+ T-cells in tumor regions and peripheral blood in mice and lab monkeys. And like the companion study, mice in these tests show no weight loss, while the raw IL-2 recipient mice lose more than 10 percent of their body weight.

“We are encouraged by the preclinical results presented at SITC,” says Asher Bio co-founder and chief scientist Ivana Djuretic in a company statement, “which demonstrate the potential for AB248 to deliver both enhanced anti-tumor efficacy and improved safety, and reinforce our confidence in AB248’s potential as a best-in-class IL-2 immunotherapy. We look forward to advancing AB248 into clinical studies across multiple solid tumor types next year.”

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