Dead cancer cells in the body are thought to help trigger an active immune response in oncology patients, particularly in combination with immunotherapy drugs. Some technologies, such as radiation and laser therapy, that kill cancer cells are being investigated for use in combination with immunotherapies.

Well-regarded oncology specialist The University of Texas MD Anderson Cancer Center has partnered with Rakuten Medical Inc. to further advance one such technology, the latter’s photoimmunotherapy platform Illuminox. MD Anderson has served as a clinical investigator site for clinical trials of the San Mateo, Calif.-based company’s most advanced candidate, ASP-1929, which is an antibody-drug conjugate based on the antibody cetuximab and a light activatable dye known as IRDye 700DX.

Immunotherapy complement?

ASP-1929 is currently in a global, 26-site phase III trial in 275 patients with recurrent head and neck squamous cell carcinoma in patients who have failed or progressed on or after at least two lines of therapy. MD Anderson is among these clinical trial sites and also participated in a phase I/II clinical trial. The partnership will include ASP-1929, as well as preclinical RM-1995, in addition to any newly advanced candidates.

“MD Anderson’s head and neck division has been our supporter from the very beginning. We have conducted a phase I/II study already; they have been involved in it,” Takashi Toraishi, COO of Rakuten Medical, told BioWorld. “They are seeking new technology, so it’s a natural extension to: why don’t we work deeper?”

Added Jeffrey Myers, chair of Head and Neck Surgery at MD Anderson, "The Illuminox technology represents a new form of therapy with the potential to selectively target cancer cells while sparing surrounding normal tissues through light-activatable antibody-dye conjugates."

Illuminox involves the use of targeted drugs such as monoclonal antibodies that are conjugated to light-excitable dyes. The drug binds to specific antigens on the cell surface of the tumor – and then the introduction of near-infrared light is intended to disrupt the membrane integrity of the cells. This results in cell death and tumor necrosis, with minimal effects on surrounding tissue. Near-infrared light can penetrate living tissue without causing any damage.

This activity is thought to induce both innate and adaptive immunity in the body. Illuminox is based on technology in-licensed from the National Institutes of Health (NIH). It was originally developed by Hisataka Kobayashi at the Center for Cancer Research (CCR), which is part of the National Cancer Institute (NCI).

Necrosis not apoptosis

“One of the unique things that Kobashi found is the induction of necrosis – not apoptosis like with chemotherapy or radiation,” said Toraishi. “Photoimmunotherapy destroys the membrane on the cancer cell, relatively quickly and simply. It has targeted the necrosis to specific cancer cells.”

Apoptosis involves a process of cell death that avoids activating the body’s inflammatory response. Necrosis, however, involves the uncontrolled release of inflammatory cellular contents; it is typically involved in cell death associated with infection and therefore can trigger the immune system.

"When the antibody-photoabsorber conjugate is injected into a mouse or human, it binds to the cancer cells [that overexpress the target for the antibody]. When near-infrared light is applied, the cells begin to swell rapidly and then burst… causing a form of rapid cell death called necrotic (or immunogenic) cell death," explained Peter Choyke, chief of CCR’s Molecular Imaging Program and a collaborator, regarding preclinical data. "Dr. Kobayashi has developed conjugates with many antibodies, and that opens up the possibility of treating a wide variety of cancers."

Primary endpoint data from the ASP-1929 phase III study was expected in December, but the company declined to speculate on a timeline now as the pandemic has slowed or halted clinical trial enrollment around the world. ASP-1929 has been granted Fast Track designation from both the FDA and received a comparable designation from the Japanese Ministry of Health, Labour, and Welfare.

In the clinic

The most recent ASP-1929 data presented from the phase II study was at the European Society for Medical Oncology (ESMO) Congress in Barcelona in September 2019. Prior to that, earlier study results were also presented at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago in June.

The ASCO data showed that of 30 treated patients with recurrent head and neck squamous cell carcinoma (rHNSCC), 43% had a response including four patients with complete responses and nine patients with partial responses. Median, progression-free survival was 5.2 months and median overall survival was 9.3 months.

The ESMO data showed that eight out of 12 patients had an induction of PD-L1 expression in tumor and immune cells. EGFR expression was maintained in residual tumors in 12 patients, as assessed by biopsies. Peripheral blood immunophenotyping suggested the activation of innate and adaptive immunity in 15 out of 18 treated patients. The ongoing, randomized, controlled phase III study has the primary endpoints of progression-free survival and overall survival.

The Illuminox platform includes a table-top device paired with near-infrared lights that is used in combination with targeted, light-activatable, antibody-dye conjugates.

Beyond ASP-1929, Rakuten also has preclinical candidate RM-1995 that targets the immune system response in an even more direct way. “It's a new molecule, and also an antibody drug conjugate using an antibody to target a different set of cells in the tumor microenvironment,” explained Toraishi. “It’s targeting the regulatory T cell, instead of the cancer cell itself. So, it's much more about the expected induction of immune response by destroying the T cell.”

Last August, Rakuten Medical raised $100 million from Rakuten Inc., which is an Internet services company that is based in Japan. That financing raised the company’s equity stake in Rakuten Medical to 22.6%. The investment was expected to move it closer to commercialization, as well as to identify and evaluate new candidates and indications for its photoimmunotherapy platform, which is expected ultimately to be used broadly.

“Our technology could have the potential to be a new modality,” summed up Toraishi. “Surgery is there, radiation is there, chemotherapy is there and immunotherapy is the fourth modality. Our technology has the potential to be the fifth going forward. I’m not convinced our technology has a competitor, we need to find the appropriate use with existing technologies.”

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