“There were also some great sessions [at SITC] highlighting different areas where there’s been a fair amount of traction, including vaccine therapies for cancer and also new cellular therapies,” Fong said.
He pointed to new drugs being developed using T-cell therapy that are changing the way scientists think about how to attack certain types of tumors.
“We now have a T-cell engager for small cell lung cancer that has been FDA approved, and so that basically resets the whole field because where people were saying before that T-cell therapies wouldn’t work in solid tumors, we now have an FDA drug for a very common and highly lethal disease,” he said. “One of the other areas that will be really exciting to see develop are T-cell engagers focused on prostate cancer, which are being developed in industry today.”
Another area in which Fong sees tremendous promise is in the development of other “bispecifics,” or molecules with two “arms” that serve related, but different, purposes. One drug featured in a late-breaking abstract at SITC binds to the receptor for programmed cell death (anti-PD) and the other is a cytokine (a “T-cell activating” molecule) called IL-2 that encourages the growth of immune system cells.
“These designer molecules that are coming to the fore are allowing us to accomplish things we would not have been able to accomplish otherwise,” Fong stressed.
Finding new targets for advanced prostate cancer
In addition to his leadership work with SITC, Fong was honored with a “Top 100 Abstracts” award and an invitation to give an oral presentation based on his lab’s current work unraveling the tumor microenvironment that protects prostate cancer cells from being attacked by immune system cells. The abstract, “Identification and therapeutic target of myeloid-mediated mechanisms of immunotherapy resistance in prostate cancer,” was presented by first author Aram Lyu, PhD, a postdoctoral research fellow in Fong’s lab.
The talk highlighted a specific type of blood cell, called SPP+ macrophages, that are found in higher numbers as prostate cancer progresses. The overexpression of SPP1, a gene that codes for the protein known as secreted phosphoprotein 1, in these cells could lead to targeted immunotherapies that can seek out these specific types of cells, potentially slowing tumor progression.
“Our findings define a resistance mechanism that many tumors known as ‘cold tumors’ use to turn off an immune response.” Fong said. In general terms, cold tumors tend to be resistant to immunotherapy due to a lack of T cells around them.
“We identified a specific myeloid cell that actually mediates the immune suppression. Once you know what’s actually causing the suppression, you can now target that cell, as opposed to the tumor being a ‘black box’ where we don’t know what’s mediating immunosuppression,” he said. “That really gives opportunities for us to select patients better for treatment, because we can now measure these myeloid cells, and so patients who have a large number of these cells could be steered to new and better treatments for their specific type of tumor.”
Fong’s research published Wednesday in the journal Nature.
Feeding CAR T cells during expansion for increased efficacy in human patients
Yapeng Su, PhD, was also honored at SITC with a “Top 100 abstract” award and an invitation to present an oral presentation. Su, a postdoctoral researcher working in Fred Hutch’s Greenberg Lab, presented the paper “Mannose supplementation: A strategy for metabolically driving a stem-like T cell program for improved tumor control.” Su, a 2024 STAT Wunderkind and a former Damon Runyon fellow honored this year with the Damon Runyon-Jake Wetchler Award, found in an experiment involving mouse models and human primary cells that addition of D-mannose (a type of sugar) to the cell culture in which CAR T cells are expanded may increase their ability to stave off exhaustion and to effectively fight cancer.
Previously, Su discovered immuno-metabolic changes in patients with COVID-19 that are strongly connected with COVID-19 severity, mortality, and long-haul syndrome. Those findings informed his current research on how cell metabolism can affect the health of the immune system. The new paper published yesterday in the journal Cancer Cell.
Additional findings in tumor cell geometry and T-cell exhaustion
Shivani Srivastava, PhD, an assistant professor in Fred Hutch’s Human Biology Division, presented the poster “PD-L1 blockade synergizes with c-Jun overexpression to boost CAR-T cell activity and mediate dramatic tumor control in an aggressive autochthonous model of lung adenocarcinoma.” (Poster presentations at scientific conferences bring together many projects under one roof, with each researcher making mini-presentations using large posters featuring their current research and data as session attendees make the rounds between presentation stations.) Srivastava, whose abstract was also honored with a “Top 100” designation at the conference, reported on her lab’s strategy to improve cell therapies for solid tumors by helping them overcome T-cell exhaustion, the state in which T cells progressively lose function when they are unable to effectively eliminate their target cells.
Srivastava’s lab found a method for genetically engineering CAR T cells that improved their function and sensitized them to enhancement with immune checkpoint inhibitors targeting PD-1, which are immune modulators that can release the “brakes” on T cell responses. PD-1 is normally expressed on T cells, and PD-L1 (programmed cell death ligand 1) is a protein found on the surface of both tumor cells and other immune cells in the tumor microenvironment that can bind to the PD-1 on a patient’s T cells to keep them from destroying the cancer cell.
In a mouse model of non-small cell lung cancer, the method utilized by Srivastava resulted in CAR T-cell numbers being boosted around 100-fold within the tumors, leading to almost complete eradication of tumor cells expressing the CAR target antigen (i.e. the specific molecule on the cancer cell that the CAR T cell is engineered to bind). The lab is now in the process of writing up these experimental results for publication.
Sarah Samorodnitsky, PhD, presented a poster based on her abstract “Persistent homology detects clinically-relevant topological structures in multiplexed spatial proteomics.” Samorodnitsky, a Fred Hutch biostatistician and postdoctoral fellow working in the lab of Michael Wu, PhD, developed a new statistical test for analyzing geometric structures in images of tumor cells, such as large masses and rings of cells.
The topological method she devised, known as TopKAT, was used to identify significant associations between the geometry of immune cell arrangements and the overall survival of patients with triple-negative breast cancer, a disease that is particularly challenging to treat because of its lack of hormone receptors on the cancer cell surface that could otherwise present targets for chemotherapy drugs. Her findings are currently being submitted to research journals for publication.
