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Trial Advances of Dual-Action Cancer Immunotherapy

Breast cancer cell

Scanning electron microscope image of a breast cancer cell. (Bruce Wetzel and Harry Schaefer, National Cancer Institute, NIH, Flickr

3 Aug. 2023. A clinical trial assessing a synthetic antibody to generate an immediate response and also generate a more durable treatment for solid tumor cancers, advanced to a mid-stage study. Bolt Biotherapeutics Inc. in Redwood City, California,, developer of the experimental cancer treatment code-named BDC-1001, says the first patients in the new stage of the trial received doses of the therapy.

Bolt Biotherapeutics creates cancer treatments that invoke the immune system, but in a more complex mechanism than most other immunotherapies. The company’s process called immune-stimulating antibody conjugate or ISAC combines or conjugates synthetic highly-targeted monoclonal antibodies with drugs designed to activate the innate or general immune system. This approach, says Bolt Bio, makes it possible to address solid tumor cancers that would be otherwise difficult to treat, and in patients where cancer does not respond to conventional treatments or recurs. And, says the company, the dual-action mechanism helps generate a longer-term response to tumors.

In this case, BDC-1001 targets cancers expressing human epidermal growth factor receptor 2 or HER2-positive proteins, often associated with breast cancer, but also found in other tumors. Bolt Bio says BDC-1001 contains a biologic similar to the monoclonal antibody trastuzumab, combined with the company’s own version of toll-like receptor proteins 7 and 8, or TLR7/8. Trastuzumab binds to and blocks HER2 activity in tumors and invokes a localized attack on tumor cells, while TLR7/8 proteins generate T-cells from the innate immune system to provide a more durable response.

29 percent clinical response to treatment

Bolt Biotherapeutics is enrolling in the clinical trial 390 individuals in the U.S., Spain, and South Korea diagnosed with breast, colorectal, uterine, and stomach cancer expressing HER2-positive proteins. The study has four parts, with the first two parts making up an early-stage trial evaluating safety, tolerability, and maximum dose for BDC-1001. However, the study has no placebo group for control purposes.

In June 2023, Bolt Bio reported initial findings from the trial at a meeting of American Society of Clinical Oncology. Results show an optimal dose of 20 milligrams per kilogram of weight, infused once every two weeks, with most adverse effects rated mild or moderate at the infusion site. In addition, 29 percent of participants show a clinical response to BDC-1001, either on its own or combined with nivolumab, a checkpoint-inhibitor immunotherapy.

The study now moves into its third part, a mid-stage trial assessing BDC-1001 as a treatment on its own for HER2-positive breast, colorectal, uterine, and stomach cancer. The study team is tracking participants for two years, again looking for adverse effects from the treatments and immune-related toxicities, but also chemical effects in the body, as well as clinical responses, duration of response, and progression-free survival time. A fourth part of the trial is scheduled to follow, evaluating BDC-1001 taken with nivolumab.

“Despite considerable advances in anti-cancer therapy,” says Bolt Biotherapeutics chief medical officer Edith Perez in a company statement, “HER2-positive tumors remain difficult to treat, and new therapeutic options are urgently needed. Our ISAC platform brings a novel mechanism with the potential to address refractory and recurrent disease to the treatment of HER2+ cancers and BDC-1001 has demonstrated promise.”

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