Xingxing Zang, PhD
Professor, Department of Microbiology & Immunology, Albert Einstein College of Medicine,
Recent advances in cancer research led by the Dana-Farber Cancer Institute and the Albert Einstein College of Medicine may lead to more personalized cancer treatments in the future. Gordon Freeman, PhD, a professor of medicine at Dana-Farber and Harvard Medical School, and XingXing Zang, PhD, a professor in the Department of Microbiology & Immunology at Albert Einstein College of Medicine, have unveiled a new pathway that can be used to activate T-cells, essential components of the immune system, to enhance the body’s natural defense against cancer. This pathway can also serve as a conduit for targeted treatments against malignant cells. These groundbreaking findings have been licensed to NextPoint Therapeutics, a small bio-tech company developing precision immuno-oncology therapies that currently are undergoing early-phase clinical trials.
Advancing Immunotherapy: Building on Foundational Discoveries
Freeman built upon his seminal work in the field of immunotherapy to achieve this latest discovery. Decades ago, he and his colleagues discovered a key interaction involving programmed death ligand-1 (PD-L1), an immune checkpoint protein that is a critical regulator (or “switch”) that cancer cells exploit to evade immune attack.
Specifically, they recognize that PD-L1 binds to programmed death protein-1 (PD-1) thus defining the PD-1/PD-L1 pathway. PD-L1 exerts an inhibitory effect on T cells by binding to the T cell co-receptor PD-1, thereby signaling the T cell not to instigate an immune system attack. In pursuing his study of the PD-1/PD-L1 pathway, Freeman discovered that the PD-L1 protein is expressed not only on normal cells but also on many cancer cells. The implication was that an agent that blocks PD-1 or PD-L1 (or a related ligand, PD-L2) could release the brakes on the immune system’s attack on cancer.
Back then, this finding led to the development of a new class of blockbuster immunotherapeutic agents, the immune checkpoint inhibitors, including Pembrolizumab (Keytruda) and Nivolumab (Opdivo), which prevent the checkpoint proteins from turning off the immune system and thus, enabling the body to fight back against the cancer. Immunotherapy drugs such as these are gentler on the body than chemotherapy and, therefore, typically are easier for patients to tolerate.
Currently, immune checkpoint inhibitors have been FDA-approved for use in treating 25 different cancer types, accounting for approximately half of all cancer-related deaths. A recent meta-analysis reported that 57.6% of advanced cancer patients (metastatic) are eligible for such PD-L1C/PD-1 drug. However, despite their broad applicability, these drugs work in only about 20% of patients, leaving a significant number of patients whose cancer does not respond to the current treatment modalities.
Identifying a More Common Target and Pathway
“We’ve discovered that cancer turns off your ‘anti-cancer’ immune response and that stopping cancer from turning off the immune response can be an effective therapy.
Gordon Freeman, PhD
Freeman and Zang searched for new ways to bridge this therapeutic gap and recently identified a novel gene, B7H7 (also referred to by its pathway, HHLA2), which is expressed on a distinct subset of tumors and is regulated by unique signaling pathways. This new gene produces a protein that occurs mainly on cancerous tumors rather than on healthy cells, making it an attractive target for future treatments. Importantly, the B7H7 protein also occurs more commonly than PDL1, which means that addressing this target has the potential to improve cancer outcomes in people who don’t respond to current immune checkpoint inhibitors.
“We’ve discovered that cancer turns off your ‘anti-cancer’ immune response and that stopping cancer from turning off the immune response can be an effective therapy,” Freeman says. “So, B7H7 is another pathway that can be used to prevent that and allow the immune response to kick in.” Since B7H7 has two receptors, one to turn off the immune system and one to turn it on, using the “on” receptor can help reverse tumor immune evasion.
A paper by Freeman and his colleagues from Dana-Farber and Beth Israel Deaconess Medical Center published in Cancer Immunology Research in 2021 explains B7H7’s mechanisms for evading the immune system and determines that it occurs independently from PD1. The authors also note that cancer cells will contain either the PDL1 or the B7H7 gene, but the two genes do not co-occur on the same tumor. Another article, also by Freeman and his colleagues, in BMC Cancer in 2023, also looks at the need to better understand how B7H7 is regulated in tumor cells in order to develop effective treatments.
Translating Insights into Therapeutic Strategies
Freeman received funding from NIH and NCI for his lab for establishing the pathway, as well as support from Dana-Farber’s Center for Innovation. This enabled Freeman and Zang to explore new ways to translate their insights into actionable therapeutic strategies for patients. This led them to form NextPoint Therapeutics, where their findings now serve as the basis for new, more personalized approaches to treating challenging cancers, including lung, kidney, and colorectal cancers.
“In just a few years, NextPoint has transformed the groundbreaking discoveries of B7H7 biology into a first-in-class, multimodal pipeline now advancing in the clinic. We are integrating foundational science of combining direct tumor killing and immunomodulation with a defined clinical biomarker to identify the right patient population for each B7H7 directed therapy,” said Ivan Cheung, MBA, Chief Executive Officer of NextPoint Therapeutics.
NextPoint’s approach also relies on high expression levels of B7H7 on tumor cells as an important biomarker to identify patients who are most likely to respond to the treatments they are developing. NextPoint is now testing one new drug (a checkpoint inhibitor) through phase one clinical trials on patients who meet this criterion with the goal of activating anti-tumor immune responses. In addition, two more drugs (a t-cell engager and an antibody-drug conjugate) will entering the clinic next year.
“NextPoint Therapeutics is revolutionizing the landscape of immune-oncology and offering new hope for a broad spectrum of human cancer patients who are unresponsive to existing PD1/PD-L1 inhibitors,” Zang adds.
The hope is that in the coming years, NextPoint will be well-positioned to bring a new layer of personalized treatments to improve outcomes for patients with hard-to-treat cancers.
Team Members
Gordon Freeman, PhD
Professor of Medicine, Dana-Farber and Harvard Medical School
