How might one gauge the contributions of selected geographical regions to cancer immunotherapy? Initially, one might assess cancer incidence and prevalence numbers, research and development expenditures, papers published in peer-reviewed journals, etc. By consulting such proxy figures, one might at least get a rough idea of how much attention one should devote to developments in different regions.
For example, market research figures suggest that roughly equal attention should be paid to developments in North America, Europe, and the Asia-Pacific regions. By 2027, the market sizes for these regions—according to Market Data Forecast—will be about $50 billion, $42 billion, and $33 billion, respectively. (The Asia-Pacific region’s market size is somewhat smaller, but this region’s growth rate is the highest, at 13.2%.)
Such broad figures tell us only so much. To learn more, we need to shift from high-level to low-level views. For example, we could get a feel for cancer immunotherapy developments in Asia by looking at the interesting things individual companies are doing. That’s what we’ll do in this article, which focuses on the advances that are being made by just a few commercially oriented institutions, all of which are located in Asia—in East Asia and Southeast Asia, to be slightly more precise. Each exemplifies creativity, drive, and humanity. Together, they make for a story that is more compelling than any high-level summation.
Drugs targeting intracellular oncoproteins
Most antibody-based cancer drugs target molecules that appear on the outer surfaces of cancer cells or are secreted by cancer cells. “Antibodies are generally believed to be too large to enter cells,” says Qi Zeng, PhD, research director at A*STAR’s Institute of Molecular and Cell Biology. “What this means is there is a large untapped pool of intracellular therapeutic targets, such as phosphatases, kinases, and transcription factors.”
For the last 20 years, Zeng has been studying the intracellular PRL3 protein that is overexpressed in many tumors but undetectable in most normal tissues for tumor-specific novel cancer immunotherapy. “In 2008,” she recalls, “we demonstrated that PRL3 antibody could specifically inhibit tumors expressing intracellular PRL3 oncoproteins.”
“We found that when cancer cells are stressed or are dying, PRL3 could be found on their surfaces or in the tumor microenvironment, enabling antibody binding and therapy,” she continues. “When PRL3-zumab was tested in multiple mouse models of cancer, we found that the antibody could bind to PRL3 to trigger an immune response against tumors, causing tumor shrinkage by as much as 90%.”
In 2015, Zeng founded an A*STAR spinoff company, Singapore-based Intra-ImmuSG (IISG), to develop PRL3-zumab, a first-in-class humanized antibody, to treat multiple PRL3-positive cancers. “The main advantage of this system,” she points out, “is that compared to the use of small chemical inhibitors in chemotherapy, antibody therapy like PRL3-zumab is more target specific, which helps to minimize off-target side effects.”
Since its inception, IISG has reached several milestones. In 2019, PRL3-zumab commenced Phase II trials for gastric and hepatocellular carcinoma in Singapore. A year later, Phase II trials were also approved by the U.S. Food and Drug Administration (FDA) and China’s National Medical Products Administration for all solid tumors.
“We are hoping to accelerate our process to recruit patients for clinical trials,” Zeng states. “Patients eligible for PRL3-zumab treatment typically have run out of all standard-of-care treatments. By then, the patients’ immune system is very weak and their response to treatment may not be as strong as we would hope.
“Targeting intracellular cancer-specific antigens would significantly enhance antibody immunotherapy [by opening] doors to a wide range of targets, including tumor-specific mutated intracellular proteins and intracellular mediators of cancer cell survival. We look forward to pioneering a new era of cancer immunotherapy.”
Light-activated tumor-targeting moieties
Many cancer therapies lack specificity and are associated with adverse side effects. “We have developed an investigational platform that makes use of photoimmunotherapy for cancer treatment,” says Takashi Toraishi, PhD, president of Rakuten Medical, a global biotechnology firm with offices in San Diego, Tokyo, Taipei City, and elsewhere. The company’s platform, which is called Alluminox, consists of a drug, a device, and other related components.
“The drug component of the platform consists of a targeting moiety conjugated with one or more dyes leading to selective cell surface binding,” Toraishi details. “The device component consists of a light source that locally illuminates the targeted cells with nonthermal light to activate the drug.
“Research is being done on therapies developed on the Alluminox platform to determine if local and systemic innate and adaptive immune activation occur due to immunogenic cell death of the targeted cells and/or the removal of immunosuppressive elements within the tumor microenvironment. In September of 2020, we received the first approval of our lead asset (ASP-1929) in Japan, and in January of 2021, we started marketing products including a device for illumination. Currently, our new treatment is provided by a growing number of sites and doctors across Japan.”
Alluminox photoimmunotherapies proceed as follows: Patients are administered a drug that binds to targeted cancer cells. After about 24 hours, a nonthermal light dose is applied, activating the drug so that it induces rapid and selective necrosis with minimal side effects on surrounding tissues.
“[Our] longer-term vision … is to generate a ‘palette’ of Alluminox conjugates targeting a variety of cancer antigens,” Toraishi declares. “Alluminox Palette is a drug discovery program that develops drugs using various tumor-targeting moieties such as antibodies, peptides, proteins, and small molecules.
“The first Alluminox Palette programs under clinical development consist of monoclonal antibody-IRDye 700DX conjugates targeting various tumor and immune cell antigens. These include ASP-1929, an antibody dye conjugate consisting of cetuximab (an anti-EGFR antibody) and RM-1995 (a conjugate of an anti-CD25 antibody targeting CD25-positive regulatory T cells).”
Toraishi notes that RM-1995 is Rakuten Medical’s second pipeline asset to reach clinical trials. He adds that the company aims to “combine multiple conjugates from the Alluminox Palette” and to “expand therapies based on the Alluminox platform for the treatment of a range of solid tumors.”
Engineered T cells targeting liver cancer
Hepatitis B virus (HBV) and hepatitis C virus (HCV) can establish persistent infections that cause chronic hepatic inflammation, leading to the development of hepatocellular carcinoma (HCC). Although antiviral therapies for HCV have delivered remarkable cure rates, curative therapies for HBV remain unavailable.
To develop new therapies against HBV—and to eliminate HBV-related HCC—the scientists at Singapore-based Lion TCR decided to conduct research into “new and more radical therapies designed to eliminate or at least stably maintain low levels of HBV replication under the control of a functional anti-host response.”
The quote above comes from a journal article (Cytotherapy 2017; 19: 1317–1324) written by Antonio Bertoletti, MD, Anthony Tan, PhD, and Sarene Koh, PhD—the scientific founder and chairman, a scientific advisor, and the director of technology and manufacturing at Lion TCR, respectively. In their work at Lion TCR, the scientists have focused on the development of T-cell therapies for HBV.
Even before Lion TCR was founded in 2015, the company’s scientists had amassed considerable experience characterizing HBV T-cell responses and T-cell receptors (TCRs) in HBV-related diseases, says Tina Wang, MD, PhD, chief operating officer and chief medical officer of Lion TCR. She adds that the scientists also provided—first in xenograft mice and then in patients—the proof of concept that HBV-specific TCR T cells can recognize HBV antigen expressed in HCC and thus treat HBV-related HCC.
“A few years later,” she declares, “the technology was demonstrated to have clinical efficacy in humans.” Moreover, Lion TCR has established the world’s largest HBV-specific TCR library, covering about 80% of the population in China, East Asia, and Southeast Asia. Finally, the company has developed LioCyx-M, an autologous T-cell product transiently modified with in vitro–transcribed mRNA encoding HBV-specific TCR.
“The advantage of our product is that the expression of the HBV-specific TCR wanes within a week after the mRNA introduced to the cells via electroporation is translated,” Wang explains. “This safety feature makes LioCyx-M suitable for use in advanced cancer patients to reduce primary tumor burden and metastases and potentially also in HBV chronic infection.”
Wang remarks that another advantage of LioCyx-M treatment is that its therapeutic efficacy is independent of tumor heterogeneity. “HBV-DNA integrations are presented in 80–90% of HBV-related HCC cells,” she elaborates. “Epitopes encoded by these HBV-DNA integrations that assemble with MHC class I molecules on cell surfaces thus serve as ideal targets for T cells as HBV-specific TCR T-cell-mediated tumor killing is independent of oncogenic status of HCC tumor cells.”
Last September, Lion TCR received clearance from the FDA for its Investigational New Drug (IND) application to assess LioCyx-M as a treatment for HBV-related HCC. At the time, the company indicated that it intended to start a Phase Ib/II multicenter study to analyze LioCyx-M as a monotherapy as well as a combination therapy with lenvatinib, a tyrosine kinase inhibitor. Since then, the company has received Fast Track Designation from the FDA for LioCyx-M for the treatment of HBV-related HCC.
Stem cell–based modeling and screening systems
“In recent years, stem cell research has made remarkable advances,” says Pengtao Liu, PhD, professor of biomedical sciences at the University of Hong Kong and director of the Center for Translational Stem Cell Biology (CTSCB). “At CTSCB, we are deriving Expanded Potential Stem Cells (EPSCs) from patients to study immune disorders and develop personalized ‘assays’ for evaluating immune responses and assessing drug candidates.”
Conventional embryonic stem cells are derived from the blastocyst, a pre-embryonic structure of about 70–100 cells that forms about five days after fertilization. In contrast, EPSCs are established from much younger pre-embryonic structures that consist of as few as four cells. Accordingly, EPSCs are more primitive than embryonic stem cells and have higher developmental potential.
“The advantages of using human EPSCs are that they are robust in culture and genetically and epigenetically stable,” Liu maintains. “They also permit efficient precision genome editing and can generate all types of cells examined so far—including engineered immune cells that may provide a new cell source for cell-based cancer immunotherapy.”
CTSCB researchers are engineering and differentiating EPSCs into genetically defined stem cell–based immune cell and tissue organoid models to study crosstalk phenomena. “At CTSCB,” Liu declares, “we strive to translate scientific discoveries into both commercial successes and healthcare benefits, and we are expecting a spinoff this year.”
PD-1-based DNA vaccines
Cancer vaccines can prevent cancer by relying on the ability of dendritic cells to induce antigen-specific immune responses. Unfortunately, this antigen process pathway is usually inefficient, resulting in low vaccine efficacy.
Determined to overcome this problem, Zhiwei Chen, PhD, DVM, professor of microbiology at the University of Hong Kong, began focusing on the development of PD-1-based DNA vaccine technology. To help commercialize the technology, Chen co-founded Immuno Cure BioTech in 2015.
“In our patented technology, the DNA vaccine encodes a PD-1-fused antigen,” says Michael Wong, PhD, Immuno Cure’s research and development director. “The unique design of the PD-1-fused antigen allows effective antigen targeting toward the PD-1 ligands expressed on dendritic cells for antigen capture and presentation.
“At the same time, the PD-1-fused antigens also enhance dendritic cell activation. These two effects facilitate a potent induction of protective immune responses against cancers, allowing substantial improvement of prevention and treatment outcomes.”
Immuno Cure’s PD-1-based DNA vaccine platform can be used in combination with immune checkpoint inhibitors to treat mesothelioma and breast cancer in preclinical animal models synergistically. In particular, PD-1-based DNA vaccination has also been shown to significantly enhance antitumor T-cell immunity, providing sustained therapeutic effect against established mesothelioma when combined with CTLA-4 blockade in mice.
Headquartered in Hong Kong, Immuno Cure maintains satellite offices in Shenzhen and Beijing. According to Wong, the company is “aiming to provide quick responses to emerging infectious diseases, cancers, and inflammatory diseases using our technology platforms at reasonably low cost for the benefit of mankind.” It is currently conducting a Phase I trial of a COVID-19 vaccine.
CAR T cells and host T cells working in tandem
Although chimeric antigen receptor (CAR) T cells are generally effective against so-called liquid cancers, they are usually defeated by solid tumors. “This is because solid tumors are a mass of cells and CAR T cells need to be able to infiltrate inside them,” says Koji Tamada, MD, PhD, professor of immunology at Yamaguchi University and president and CEO of Noile-Immune Biotech. “Furthermore, solid tumors are highly heterogeneous, and most CAR T-cell products recognize only one cancer antigen target.”
“When I started my professorship at Yamaguchi University in 2011,” Tamada relates, “I knew I had to find strategies to enhance accumulation of CAR T cells and to enhance polyclonal T-cell response.” In 2015, Tamada established Noile-Immune Biotech in Tokyo. In 2018, Tamada led a team of Yamaguchi- and company-affiliated scientists that engineered CAR T cells to express interleukin-7 (IL-7) and CCL19. The scientists reported (Adachi et al. Nature Biotechnology 2018; 36: 346–351) that in mice, these CAR T cells “achieved complete regression of preestablished solid tumors and prolonged mouse survival, with superior antitumor activity compared with conventional CAR-T cells.”
“Our choice of IL-7 and CCL19 stems from our understanding that T-zone fibroblastic reticular cells in the lymph nodes produce these biomolecules to recruit T cells,” Tamada details. “We wanted to exploit a natural way to make our CAR T cells more powerful. This is the basis of our Proliferating-Inducing and Migration-Enhancing (PRIME) technology.”
In addition to the efficacy from administered CAR T cells, PRIME technology also boosts endogenous T-cell and dendritic cell responses, with the potential to convert “cold” tumors to “hot” tumors. This is a powerful approach to induce host T-cell responses against target-negative cancer cells and to generate long-term memory T-cell responses.
Noile-Immune Biotech currently has three products in Phase I trials—two are licensed exclusively to Takeda Pharmaceuticals, and one is under development in-house. The company is also collaborating with other companies working on autologous immune cell derivation and gene editing.
“Our five-year vision for the company,” Tamada declares, “is to combine and expand PRIME technology with other promising technologies such as induced pluripotent stem cell–derived T cells and natural killer cells to improve care for