Cell Therapy: Harnessing Cells of the Immune System to Fight Cancer

One of the most exciting developments in the fight against cancer is the advent of cell-based immunotherapy, a personalized treatment that kills cancer by using the patient’s own immune cells. To date, cellular therapies have been approved for people with certain blood cancers, but cell therapy for solid tumors has yet to reach that same milestone. With solid tumors comprising about 90% of all cancer diagnoses, more research on cell therapy technology and scalable production could expand this treatment to a much larger number of people with cancer.

Cell therapy uses living cells as a drug to treat disease. When used to treat cancer, cell therapy takes advantage of the immune system’s intrinsic ability to seek out and destroy abnormal cells in the body. This approach goes by many names, including immune cell therapy and adoptive cell therapy, but they all refer to the same type of cancer treatment. Specialized immune system cells are either 1) engineered to recognize unique tags on an individual’s cancer or 2) selectively isolated from a patient’s tumor and grown in large numbers in the laboratory and given back to the patient by intravenous infusion.

Over the past decade, NCI-funded studies have established cell therapy as a viable cancer treatment strategy, and NCI-supported researchers continue to refine and expand on that work. Today, there are 36 NCI-Designated Comprehensive Cancer Centers with cell therapy programs and the Food and Drug Administration (FDA) has approved six cell therapies to treat blood cancers. However, developing cell therapies for solid tumors that will selectively attack cancer cells, persist in the body, and overcome a tumor’s ability to hide from the immune system has been notoriously difficult. Cell therapy is also very expensive and difficult to produce in scalable quantities with the technologies available.

Fundamental laboratory research is needed to break through these barriers to expanding cell therapy. With research findings in hand, additional federal funding will enable early-phase clinical trials that test novel cell therapy approaches. The federal government also plays an important role in providing the infrastructure and shared resources that facilitate cell therapy studies at research centers and clinical trial sites around the country.

If we can adapt cell therapy to successfully treat solid tumors plus sustain NCI-supported infrastructure development, many more patients could benefit from this individualized, highly targeted cancer treatment.

Targeting solid tumor cells without harming healthy tissue

A key requirement for cell therapy is the identification of molecules that are found predominantly, or only, on cancer cells. The lack of cancer-specific molecules that mark solid tumors has been a major barrier to bringing cell therapy to more people with cancer. This is particularly challenging for childhood cancers because tumor cells and healthy cells in children share many of the same molecular tags.

Over the past few years, NCI investments have bolstered tumor marker discovery for solid tumors, including those that arise in children. In 2019, an NCI-funded team led by investigators at Stanford University shrank pediatric tumors that were grafted into mice by priming T cells (one kind of immune cell) to recognize a protein called B7-H3 found on the surface of some pediatric cancer cells. More recently, NCI intramural researchers developed three cell therapies for adults that target the cancer cell markers GPC2 and mesothelin in mice and GPC3 in humans to treat neuroblastoma, lung cancer, and liver cancer, respectively. With a cancer-specific surface protein library in hand, researchers can explore how to target solid tumor cells more effectively.

While this is a promising area of research, there are more challenges to overcome. Further research is needed to identify who will benefit most from cell therapy and how to make a person’s cancer more vulnerable to these treatments.

Studies to address these challenges are underway. In an NCI-funded first-in-human trial involving three participants with treatment-resistant cancer, researchers from the University of Pennsylvania and Stanford University School of Medicine genetically engineered T cells to recognize each patient’s specific cancer and to ignore immune-suppressing signals coming from the tumors. The modified T cells were safe to use and persisted in humans, and they were able to target the tumors in each of the three patients.

Investing in a full set of tools for the cell therapy toolbox

In the same way that a tool is designed for specific functions, an immune cell is made for specific tasks. You would not use a hammer to turn a screw, and you would not use an immune cell that detects surface proteins to target a cancer cell’s internal machinery. That is why we need to add multiple cell types to the cell therapy toolbox.

Chimeric antigen receptor (CAR) T cells have been a favorite for cell therapy applications and have been used in all FDA-approved cell therapies to date. However, other immune cells, including tumor-infiltrating lymphocytes (TILs) developed to treat melanoma and breast cancer, show promise.

Each approach has benefits but also challenges to overcome. Continued investments will help us optimize these approaches, learn which tools work best for each cancer type, and potentially add more cell types to the cell therapy toolbox.

• chimeric antigen receptor (CAR) T cells: A patient’s own T cells are modified in the lab with a receptor, called CAR, that is designed to recognize molecules, called antigens, on the surface of cancer cells. More research is needed to establish a library of tumor-specific antigen markers for every cancer type.
   
• engineered T-cell receptor cells: A patient’s own T cells are engineered with a receptor that detects cancer-associated proteins that are processed inside the cancer cell and presented on its surface by a specialized protein complex. More research is needed to develop synthetic biology approaches that build safer, more effective, longer-lasting engineered T-cell receptor cells to treat solid tumors.
   
• tumor-infiltrating lymphocytes (TILs): T cells that have already invaded a patient’s tumor are removed and grown in large numbers in the laboratory to infuse back into the patient. More research is needed to overcome immune-suppressing signals so that TILs and all other cell therapies are more effective.
   
• natural killer (NK) cells: Like T cells, NK cells can be modified to express receptors that target the destruction of cancer cells. As their name implies, natural killer cells eliminate pathogens and abnormal cells. More research is needed to develop these newer cell therapy technologies and overcome early challenges, such as helping cells survive once reintroduced into the patient.

With more research, we can envision cell therapy approaches that are tailored to each cancer type. NCI’s notable foray in this area is the NCI Center for Cell-Based Therapy, a Cancer Moonshot℠ project. The center is a multidisciplinary community within the NCI intramural program that facilitates and accelerates the further development of cutting-edge cell therapy approaches.

Boosting infrastructure support for rapid cell therapy advancements

NCI is making the infrastructure investments needed to establish cell therapy as a viable treatment option for more cancer types. For example, NCI will grow and promote the Cancer Adoptive Cellular Therapy Network (Can-ACT). This new network fills a significant gap in the research community: providing support for early-stage clinical testing of novel cell therapies for solid tumors in adults and children. To produce the cell therapies needed for these studies, the Frederick National Laboratory for Cancer Research offers standardized cell therapy manufacturing to researchers across the United States.

These NCI-supported resources are critical for meeting the technical and manufacturing challenges that cell therapy researchers face today. Sustained NCI support will help streamline cell construction technologies and develop standardized cell handling procedures. These processes are essential components to rapid and safe cell therapy production—and to a future where we can offer cell therapy to more patients.