The next chapter in immunotherapy research

The notion of harnessing our body’s natural defenses to prevent illness has been around for more than 135 years. Over the last few decades, significant steps forward in research have resulted in exciting breakthroughs in immune-based cancer treatment, also known as immunotherapy. Because of these advancements, this relatively new therapy takes its place alongside the other pillars of cancer care: chemotherapy, radiation, surgery and targeted therapy.

Chimeric antigen receptor T-cell therapy is a form of immunotherapy that uses modified versions of the patient’s cells to find and fight cancer cells. And while CAR T-cell therapy has emerged as a superstar in cell therapy, it’s not the only shining star in the field. In fact, it’s just the beginning of an incredible new chapter in immunotherapy as novel developments continue to emerge.

CAR T-cell therapy currently treats cancer types that are relatively rare, such as leukemias, myelomas and lymphomas. Solid tumors, like those found in colon, breast or lung cancer, are far more common but less responsive to CAR T-cell and other immunotherapy treatments. Researchers at The University of Kansas Cancer Center are among those worldwide working to change that dynamic.

Many blood cancers arise from B cells (a type of white blood cell) that no longer work like they should. On the surface of these cells is a molecule, CD19, which is a widely used target in CAR T-cell therapy, as it’s not found on other healthy cells. This means CAR T-cell therapy spares other parts of the body, such as your brain or heart, during treatment.

While CD19 is uniquely identifiable on B cells, identifying a target molecule for T cells that is restricted to the cancer cells in solid tumors is more challenging. This makes immunotherapy less effective for these types of cancer, but scientists across the globe are finding ways to overcome this challenge by:

• Working to identify tumor-specific molecules on the surface of the cell.
• Developing a CAR T cell that attacks only when 2 otherwise normal molecules, which are ordinarily never seen together but are present in certain types of cancers together, are detected. If there’s only 1, such as in normal tissues, the CAR T cell is not activated – however, when both are present, the CAR T cell engages and destroys the cell. This strategy results in targeting molecules that are on normal, healthy tissues without causing damage to those tissues.
• Creating ways to arm T cells with molecules to counteract the solid tumor’s hostile microenvironment that supports cancer growth, allowing the immune system to enter and do its job.

CAR T-cell therapy has made waves in cancer care, but it’s not the only cell-based immunotherapeutic strategy out there.

• Investigators have genetically modified other cell types of the immune system to express CAR; one example is the natural killer (NK) cell. Similar to the CAR T cell, the NK-CARs can be modified to kill cancerous cells in several unique ways, and scientists are developing more strategies each day to further genetically modify these cells and successfully eradicate a broad array of cancers.
• The 2020 Nobel Prize in Chemistry recipients, Drs. Emmanuelle Charpentier and Jennifer A. Doudna, discovered a vital tool in gene editing: the CRISPR/Cas9 genetic scissors. With these scissors, researchers can precisely alter DNA, which will continue to improve the efficacy and safety of all cell-based cancer therapy.
• Scientists are exploring how to modify T cells and their receptors to better ward off cancer. When operating properly, our T cells recognize antigens only in the context of our human leukocyte antigen (HLA) complex system. In the natural state, certain types of cells, such as dendritic cells, digest components of cancerous cells and present small pieces of the cancer cells on the surface of the T cell in the context of the HLA system. This significantly restricts the types of molecules that native T-cell receptors can recognize. In contrast, CAR T cells are engineered to recognize any molecule on the surface of the cancer cell independent of the HLA system, greatly expanding targets for attacking these cells. This allows the CAR T cells to detect what the care team wants them to see, not just what the immune system has flagged. This approach is being studied today in 25 clinical trials at The University of Kansas Cancer Center.

Currently, the super-charged CAR T cells used to treat patients with cancer have come from the patients themselves. However, using the cancer patient’s own T cells may not be optimal. An alternative strategy would be to use a normal, healthy person, who has never been diagnosed with cancer or exposed to chemotherapy, as a T cell donor. This strategy would be complicated by rejection of the donor T cell by the patient or potentially harm the patient through an attack of the patient’s tissues by the patient’s T cells, known as graft versus host disease (GVHD). However, using donated T cells may have just gotten significantly easier. Using CRISPR-Cas9 gene editing, physicians can clip out the donated T cells’ receptors that would cause GVHD, as well as edit out components of the HLA system to prevent rejection of the CAR T cells by the patient’s immune system. The University of Kansas Cancer Center was the first to enroll a patient in a multicenter, multinational clinical trial using healthy, off-the-shelf CAR T cells led by Dr. Charpentier’s company. These off-the-shelf, engineered cells have been successfully used to treat patients with relapsed refractory blood cancers, achieving significant responses and complete remissions. These results were presented at an international meeting in Paris in April 2023 by Dr. Joseph McGuirk, representing The University of Kansas Cancer Center.

Developing and administering CAR T cell and other engineered cell therapies requires a team of specialized experts and an infrastructure to match.

The University of Kansas Cancer Center, home to the largest and most experienced blood and marrow transplant and cellular therapeutics program in the region, is uniquely positioned, with our fellow National Cancer Institute-designated comprehensive cancer centers, to lead the charge in this new chapter of immunotherapy treatments. The University of Kansas Cancer Center was the first of 27 sites worldwide to enroll patients in the multinational phase 2 study, which led to the approval of the second-ever CAR T-cell drug, KYMRIAH®.

That was in 2017. Fast forward to today, and our physician-scientists are spearheading their own immunotherapy investigator-initiated trials. These efforts give us hope in defeating hard-to-treat cancers.

Investigators at The University of Kansas Cancer Center, in partnership with the NCI and Children’s Mercy Hospital, are working to produce CAR T cells that target multiple cell surface molecules. This means that if the tumor escapes detection by no longer expressing a targeted cell surface molecule, the CAR T cell has been engineered to recognize 2 other molecules on the cell surface, circumventing the tumor’s escape. This example underscores the value of being an NCI-designated comprehensive cancer center.

Our researchers are also working to find ways to overcome the potentially dangerous side effects of CAR T and other cell therapies. Numerous efforts are taking place to address toxic side effects such as cytokine release syndrome and neurologic toxicity. These highlights represent but a fraction of the remarkable research underway at The University of Kansas Cancer Center. We are moving toward a future of more precise and effective therapies than those that have been used for decades. That future looks very bright indeed.