New research from Memorial Sloan Kettering Cancer Center (MSK) decodes how mesothelioma evades immunotherapy; shows why a common kidney cancer treatment combination falls short; and supports a free, open-source AI-driven drug discovery initiative.
Decoding how mesothelioma evades immunotherapy
A team led by scientists from MSK has discovered why some pleural mesothelioma tumors stop responding to immunotherapy — and found potential ways to fix it. Pleural mesothelioma, a deadly cancer affecting the lining of the lungs, is very difficult to treat if it’s discovered after it has spread or if comes back after surgery.
The research focused on finding better ways to treat mesothelioma with CAR T therapy — an engineered cell therapy that can successfully treat many blood cancers but is much less effective against solid tumors like mesothelioma. It also sought to understand why patients eventually develop resistance to immune checkpoint inhibitor agents such as anti-PD1 drugs — for example, pembrolizumab (Keytruda®) — even when they initially respond.
In the new study, the researchers grew mesothelioma tumors in mice, treated them with a low dose of CAR T cells or anti-PD1 drugs, then analyzed the tumors that came back, comparing them to those that did not. Through this work, they discovered that resistant tumors had low levels of a tumor suppressor gene called NF2. This gene generates a protein called Merlin, which normally acts like a brake on cancer growth. Additionally, they learned that when NF2 was intentionally removed from cancer cells in the lab, tumors became resistant to both CAR T therapy and checkpoint inhibitor therapy.
When the team analyzed tumor samples from mesothelioma patients, they found that those with NF2 loss were less likely to respond to immunotherapy as well.
“Most importantly, we explored therapeutic agents that are already in clinic that can be combined with immunotherapy to transform therapy-resistant tumors to therapy-sensitive,” says MSK physician-scientist Prasad Adusumilli, MD, the study’s senior author. “Based on what we learned, we may eventually be able to develop combination treatments that target the immune environment so that more patients can benefit from immunotherapy.”
Dr. Adusumilli and his colleagues also recently published a case study of a patient with sarcomatoid mesothelioma, an aggressive mesothelioma subtype, who developed resistance to immunotherapy at one location only. They coined the term “regional immunosuppression” to describe the phenomenon. By analyzing the patient’s tumor, they found that cancer can develop resistance to immunotherapy through coordinated reprogramming of multiple cell types simultaneously, essentially corrupting the tumor’s immune environment. The researchers identified several specific molecular targets that could be blocked with next-generation therapies to potentially overcome this resistance.
Read more in Med and Journal for ImmunoTherapy of Cancer.
Why a common kidney cancer treatment combination falls short — and a potential path forward
Combinations of two types of drugs are widely used to treat clear cell renal cell carcinoma, the most common form of kidney cancer. Drugs called VEGFR-TKIs cut off a tumor’s blood supply, while immunotherapies boost the immune system to fight the cancer.
While these combinations can be effective, their benefits rarely last as long as immunotherapy alone. Now, a new MSK study sheds light on why — and points toward ways to refine treatment strategies. The work was led Ari Hakimi, MD, a physician-scientist in MSK’s Human Oncology and Pathogenesis Program, and senior research lead Lynda Vuong, PhD.
The study used a genetically engineered mouse model of treatment-resistant kidney cancer, combined with tumor samples from patients who had received treatment before surgery, to investigate how the tumor environment changes in response to different therapies.
The findings reveal a paradox at the heart of the combination approach. This type of kidney cancer is driven by genetic mutations that make tumor cells behave as if they are oxygen-starved — even when they are not. But VEGFR-TKIs, which work by cutting off the tumor’s blood supply, create genuine oxygen deprivation (hypoxia) within tumors.
In the short term, true hypoxia can signal that the treatment is working. The team identified a specific type of immune cell, called an SPP1+ macrophage, that gets recruited to the tumor in response to low oxygen and appears to serve as a marker of treatment response.
But when hypoxia is present before treatment begins or if it persists too long, it can lead to worse outcomes — and in mouse models, prolonged hypoxia accelerated the spread of cancer to other parts of the body.
“These two drugs appear to work largely independently rather than boosting each other’s effects — and our study helps explain why treatment that includes VEGFR-TKIs doesn’t last as long as immunotherapy alone, even in other cancer types,” Dr. Hakimi says. “That understanding could help us design smarter treatment combinations and better match patients to the therapies most likely to work for them.”
Read more in Cancer Cell.
MSK expertise supports free, open-source AI-driven drug discovery initiative
An international consortium that includes MSK expertise is charting new ground in open-source, artificial intelligence-driven drug discovery.
The OpenBind Consortium recently released its first major dataset focused on Enterovirus A71 (EV-A71), a leading cause of hand, foot, and mouth disease, which can lead to significant neurological complications.
The dataset pairs protein structures with binding affinity measurements that quantify how strongly drug molecules stick to target proteins — essentially showing how well potential drugs lock onto the disease targets.
MSK computational biologist John Chodera, PhD, an expert in AI-driven drug design, co-founded the OpenBind project, which collaborates closely with the AI-driven Structure-enabled Antiviral Platform (ASAP) for which he is a principal investigator. ASAP is focused on the discovery of drugs to prevent future pandemics with the goal of globally equitable and affordable access, and is funded by a $110 million grant from the National Institute of Allergy and Infectious Diseases.
The OpenBind project, which was launched with an £8 million grant from the UK government, aims to accelerate structure-based drug design — including cancer therapeutics — by curating protein-ligand structure-affinity datasets designed for training next-generation AI models and making results freely available to researchers worldwide.
“This is AI-supported research that aims to enable smarter, faster drug discovery — building the computational tools and datasets that will help us design better medicines for patients,” Dr. Chodera says.