[SITC 2024] GI Innovation’s therapies aim to enhance CAR-T durability and overcome tumor immune suppression

HOUSTON, TX -- By Lee Han-soo/Korea Biomedical Review correspondent -- GI Innovation is driving forward two biologics, GI-101A and GI-108, each addressing critical challenges in cancer treatment -- the durability and persistence of CAR-T cells and the immune-suppressive tumor microenvironment.

The company presented the two poster studies regarding the treatments at the Society for Immunotherapy of Cancer (SITC) 2024 conference, held from Nov. 6-10 in Houston, Texas. Established in 1984, SITC is the world's largest conference dedicated to cancer immunotherapy, bringing together over 4,600 clinicians, scientists, and researchers from 63 countries to advance cancer treatment through immunotherapy development.

As a result, Korea Biomedical Review met with GI Innovation Chief Scientific Officer Jang Myoung-ho and VP of Clinical Development Yun Na-ri about how the company aims to reshape treatment outcomes for patients facing relapse or resistance to the treatments.

"The immunotherapy landscape is evolving rapidly, but significant challenges remain," Yun began. "With our GI-101A program, we're addressing one of the most critical issues in CAR-T therapy – the challenge of maintaining long-term responses."

The company's GI-101A, a novel CD80-IgG4-IL2v2 fusion protein, has demonstrated promising results in a lymphoma model by supporting CAR-T cell expansion and enhancing the number of memory T cells, essential for lasting immune defense.

"In our lymphoma models, we observed that while CAR-T therapy alone showed initial responses, tumors typically recurred after day 20," Yun said. "However, when combined with GI-101A, we achieved complete remission."

What's particularly exciting is that even in cases where tumors recurred, administering GI-101A could rescue the response, Yun added.

Jang agreed. 

"This isn't just about extending survival," Jang emphasized. "What we're seeing in our preclinical models is unprecedented – maintaining responses for over 100 days."

Typically, in mouse models, CAR-T cells show recurrence around day 18, and this data has generated significant interest from clinicians, Jang added. 

Jang also stressed that a major obstacle in CAR-T therapy is the rapid decline in CAR-T cell levels post-infusion, making it difficult to maintain a long-term therapeutic effect.

“With GI-101A, we’re not just increasing CAR-T cell numbers, we’re enhancing the quality of those cells to make them more effective over time,” Jang said.

Preclinical data showed that GI-101A boosted both CD4+ and CD8+ CAR-T cells, ultimately achieving complete remission in test models.

Also, GI-101A maintained elevated CAR-T levels after tumor rechallenge, highlighting its potential as a consolidation therapy that could extend the duration of CAR-T efficacy and improve relapse rates.

"When we looked at the T cell populations, we found that GI-101A significantly increased central memory and effector memory T cells," Yun detailed. "This is crucial because these memory populations are essential for maintaining long-term anti-tumor responses."

The candidate not only increases the quantity of T cells, but improving their quality, she added.

Jang emphasized that the persistence of CAR-T cells is crucial for effective treatment.

“CAR-T cells are powerful, but they diminish too quickly in the body, which often limits their impact,” Jang said. “By promoting memory T cells, GI-101A strengthens the immune response, providing a robust, sustainable defense against cancer cells.”

This reinforcement of CAR-T cell persistence is particularly evident in the rise of central and effector memory T cells, which are more resilient and have greater potential for a prolonged anti-cancer effect.

According to Yun, the development of GI-101A could offer a significant improvement for patients undergoing CAR-T therapy, especially in the context of relapse, where traditional treatments struggle to keep up.

GI-101A’s timeline includes collaborations with prominent Korean academic centers like Asan Medical Center, working closely with key opinion leaders in CAR-T therapies.

Early next year, GI Innovation plans to start its initial human trials with GI-101A in combination with CAR-T therapy, particularly focusing on blood cancers with high relapse rates.

As for GI-108, this candidate combines an anti-CD73 antibody with an IL-2 variant to target immune suppression—a major barrier in the tumor microenvironment—particularly in solid tumors such as pancreatic, esophageal, lung, and stomach cancers.

CD73, an enzyme involved in adenosine production, contributes to immunosuppression, preventing the immune cells from effectively targeting cancer.

"CD73 is highly expressed in several challenging cancers, including pancreatic and lung cancers," Yun said. "Patients with high CD73 expression typically have poor survival rates and our approach with GI-108 is unique as we're not just blocking the adenosine pathway, we're also stimulating immune cells."

Yun explained that adenosine is essentially a shield that cancer cells use to hide from the immune system.

"With GI-108, we’re breaking down that shield while simultaneously activating T cells to increase their cancer-fighting capacity," she said. 

GI-108’s dual-action mechanism not only blocks adenosine production but also triggers T-cell activation and proliferation, aiming to enhance the immune response in adenosine-rich conditions—a challenging feat that Yun described as a “breakthrough approach.”

GI-108 stands apart from existing treatments by employing an IL-2 variant that can function in adenosine-rich environments, where traditional immunotherapies lose effectiveness. The initial focus will be on lung and pancreatic cancers due to high CD73 expression, making them ideal candidates for this immunocytokine’s dual-action mechanism.

“What sets GI-108 apart is its ability to activate T cells even when adenosine levels are high, which is usually a major impediment,” Jang said. “We’re seeing this drug engage immune cells more effectively than other CD73 inhibitors currently in the pipeline, showing real potential in cancers that haven’t responded well to other forms of treatment.”

Jang shared the company's strategic vision for the candidate. 

"We recently received regulatory approval for our clinical trial, and we're collaborating with leading medical centers in Korea," he said. "The enthusiasm from clinical investigators has been remarkable. Professor Cho Byoung-chul Cho at Severance Hospital has expressed particular interest in leading the lung cancer studies."

"What's particularly exciting about our approach is its potential in combination with existing therapies," she said. "For instance, in pancreatic cancer, where treatment options are limited, we've seen encouraging results."

In the company's previous studies with GI-101, we observed a 73 percent reduction in tumor size in a patient who had failed multiple prior therapies, she added.

Yun stressed that the company's approach to development is distinctly biomarker-driven.

"We're not taking a one-size-fits-all approach," Yun emphasized. "We're carefully selecting patients based on biomarkers, particularly CD73 expression and this targeted approach could significantly improve response rates."

Both Jang and Yun stressed that they see GI-108 as a game-changer, particularly for cancers with high CD73 expression, where immune responses are often stifled by adenosine.

Looking ahead, Jang expressed confidence in the company's trajectory.

"The next six months will be transformative for GI Innovation. We have multiple potential catalysts ahead, and the interest from global pharmaceutical companies has been significant," he said. "We've had about five meetings with major companies during SITC."