February 11, 2021
The concept of harnessing our body’s natural defenses to ward off disease has been around for more than 135 years. Over the last few decades, incremental steps in basic research have launched exciting breakthroughs in immune-based cancer treatment. Thanks to our ever-growing knowledge in this field, immunotherapy has found its place among cancer care’s original four pillars, which are chemotherapy, radiation, surgery and targeted therapy.
Chimeric antigen receptor (CAR) T-cell therapy uses re-engineered versions of a person's own cells to find and fight cancer cells. T-cells are extracted from the patient, genetically engineered and returned to the patient's bloodstream to seek and destroy remaining cancer cells. CAR T-cell therapy has emerged as a superstar in cell therapy, but it is not the only bright spot in the field. In fact, I believe it’s just the beginning of an incredible new chapter in immunotherapy.
In a review published in 2020, The Lancet Oncology, I chronicled decades of immune-based research leading to CAR T-cell therapy, noting the groundbreaking work of James Allison and Tasuku Honjo, who jointly received the Nobel Prize in Physiology or Medicine in 2018 for advancing the study of checkpoint inhibitors. Drs. Allison and Honjo discovered T-cell inhibitory signaling pathways that, when activated, prevent effective cancer immunity. Dr. Allison found that a protein on the surface of T-cells, called CTLA-4, functions as an immune checkpoint and desensitizes immune response. In a separate effort, Dr. Honjo and his team identified another molecule that influences T-cell activity. Called PD-1, it sticks to a molecule on cancer cells called PD-L1. When these two molecules join up, immune cells lose their ability to detect tumor cells.
Their work, which started in the 1990s, led to a stunning revelation: Both CTLA-4 and PD-1 can be manipulated by drugs called checkpoint inhibitors. Without these central findings, immunotherapy as we know it would not exist.
A different approach to solid tumors
The cancers I treat are relatively rare malignancies, including leukemias, myelomas and lymphomas. Solid tumors, such as cancers of the colon, breast, lung and prostate, make up a greater share of such diagnoses. For example, about 190,000 cases of prostate cancer are diagnosed each year. Generally, solid cancers have been less amenable to CAR T-cell and other immunotherapy treatments. Researchers at institutions across the world, including The University of Kansas Cancer Center, are working to change that.
Many hematologic malignancies arise from B cells (a type of white blood cell) gone awry. On the surface of the B cells sits a molecule, called CD19. This molecule is the most widely used target in CAR T therapy. We can target acute lymphoblastic leukemia and many lymphomas by zeroing in on CD19. An important aspect of this molecule is that it's not expressed on normal tissues, which means CAR T therapy will not target other, healthy parts of the body, like your lungs, brain or heart.
The target antigen is not as clear in solid tumors, which express a wide variety of proteins on their surface. But scientists are extraordinarily creative. Out of this major hurdle has come several initiatives. First, researchers are working to identify tumor-specific molecules on the cell surface. Second, we are targeting molecules that exist on both the cancer cell and the normal healthy tissue. Molecules expressed in cancer cells may be grouped; in healthy tissue, they are expressed as a single molecule. Scientists are working on a CAR T-cell that attacks only if two or three of these cancer molecules are detected. If it sees just one molecule, it does nothing and moves along.
Finally, we are taking a close look at the tumor microenvironment, a custom home built by cancerous cells, with the ideal specifications to support cancer growth. Molecules issued from the microenvironment halt any T-cells entering their home. Clinicians and scientists are developing strategies to arm T-cells with molecules that counteract that inhibitory environment and allow the immune system to enter and do its job.
These efforts – and so many more – represent years of research conducted by many people across the globe. It was just a decade ago we were witnessing early success with CAR T-cell therapies in blood cancers.
Thinking beyond CAR T-cells
CAR T-cell therapy has certainly made a huge impact in the field of cancer care, but is by no means the only cell-based immunotherapeutic strategy to fight cancer. Investigators have discovered we can arm natural killer (NK) cells, another type of immune cell, with chimeric antigen receptors. That’s the beauty of the CAR structure – you can modify NK cells, T-cells, macrophages and other cells to kill cancerous cells in several ways. We are learning more each day.
Recipients of the 2020 Nobel Prize in Chemistry, Drs. Emmanuelle Charpentier and Jennifer A. Doudna discovered a vital tool in gene editing: the CRISPR/Cas9 genetic scissors. Using these, researchers can alter DNA with tremendously high precision. The technology has transformed and led to important discoveries in basic research and in the clinic. The genetic engineering of T-cells holds huge potential to improve the efficacy and safety of T-cells-based cancer therapy.
Scientists are exploring how a native T-cell and its receptor may be modified to better ward off cancer. Usually, our T-cell recognizes antigens only in the context of our human leukocyte antigen complex, or HLA, system. Dendritic cells are antigen-presenting cells, and their primary function is to gobble up viruses and cancerous cells. What’s left of them is placed on the surface of the HLA so the T-cell knows to kill it the next time they cross paths. However, the native T-cell receptor can only see molecules inside the cell that are chewed up and presented in the context of the HLA system. The CAR T-cell, on the other hand, can see anything on the cell surface that it’s been coded to see – but it can’t see inside of the cell. As a therapeutic approach, we keep the native T-cells, but create T-cell receptors (TCRs) designed to detect what we want them to see, not just what the immune system has flagged. This approach, in combination with checkpoint inhibitor drugs, is being studied at institutions across the country, including The University of Kansas Cancer Center.
Exploring 3rd-party T-cells
Currently, the super-charged T-cells used to treat cancer come from the patients themselves. There are a few reasons to reconsider that strategy ... first, their T-cells allowed for cancer to grow. Second, most patients undergo chemotherapy and/or radiation therapy, which is taxing on the T-cells. Healthier, younger T-cells from healthier, younger donors might be the answer. There are challenges, however, in using donated T-cells. Without any modifying, they will likely be recognized as foreign and promptly rejected by the recipient’s immune system. Worse, the T-cells themselves may recognize the body as a foreign object and attack it, a potentially deadly condition called Graft-versus-Host Disease.
Using CRISPR-Cas9 gene editing, you can clip out the donated T-cell’s receptor that will cause Graft-versus-Host Disease, as well as the recipient’s HLA system that will recognize the donated T-cell as foreign. At our cancer center and other select centers in the nation, we are using healthy, off-the-shelf CAR T-cells to treat patients. We were the first to enroll a patient on a multicenter, multinational trial led by Nobel Prize winner Dr. Charpentier’s company. In the future, we will see these off-the-shelf engineered cells used in conjunction with the small signal transduction inhibitors that modulate signaling pathways inside the cell.
Leaders in the field
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 is home to the largest and most experienced blood and marrow transplant and cellular therapeutics program in the region. This positions the cancer center, working with our fellow National Cancer Institute-designated cancer centers, to lead the charge in this new chapter of immunotherapy treatments. For example, KU Cancer Center was the first of 27 sites around the world to enroll patients in the multi-national phase 2 study, which led to the approval of the second-ever CAR T-cell drug, KYMRIAH™.
That was in 2017. Fast forward to present day, and the cancer center has 20 active CAR T-cell clinical trials spanning the spectrum of blood cancers and solid tumors. In addition, there are 14 other cell therapy trials, including trials studying T-cell receptors in solid tumors.
Our physician-scientists are spearheading their own immunotherapy investigator-initiated trials studying a variety of cancers including advanced metastatic prostate cancer, led by Dr. Rahul Parikh, and human papillomavirus (HPV)-associated head and neck cancer, led by Dr. Prakash Neupane. KU Cancer Center radiation oncologist David Akhavan, MD, PhD, is generating CAR T-cells to target tumors in the brain. His work involves precisely routing the CAR T-cells to blood vessels feeding the tumors. These efforts give us hope in hard-to-treat cancers.
Investigators at The University of Kansas Cancer Center are working with the National Cancer Institute to produce CAR T-cells that target multiple cell surface molecules, such that if the tumor can escape detection by no longer expressing a targeted cell surface molecule such as CD19, we’ve engineered it to recognize 2 other molecules on the cell surface, e.g. CD-20 and CD-22. With The University of Central Lancashire (UK), we jointly hired a scientist who shares appointments between our 2 institutions. This partnership started with a conversation from a visiting speaker, and now it may lead to exciting international collaborations! These examples underscore the value in being a National Cancer Institute-designated academic medical center.
It’s important to note that we must also find ways to overcome the potentially dangerous side effects of CAR T and other cell therapies. There are numerous efforts taking place to address toxic side effects such as cytokine release syndrome and neurologic toxicity.
What I’ve highlighted here is just a fraction of the remarkable research activity in the field. We are moving toward a future of more precise, more effective therapies than our traditional chemotherapies and radiation therapies that have been used for decades. It is truly an exciting time to be a researcher and a clinician.