CAR-T immunotherapy has revolutionized the treatment landscape for blood cancers like leukemia, lymphoma, and multiple myeloma. With six FDA-approved therapies bracing the therapeutic marketplace, CAR-T has generated significant buzz within the medical and research communities. To date, over 30,000 patients with few remaining treatment options available have been treated with CAR-T, leading to long-lasting remissions.
Amidst the buzz surrounding CAR-T lies another lesser-known, up-and-coming treatment option — CAR-NK immunotherapy — that can help overcome some of the technological hurdles of CAR-T.
CAR-T vs. CAR-NK
The crux of both CAR-T and CAR-NK therapies lies in the extraordinary beauty and complexity of the human immune system. CAR-T harnesses a type of immune cell known as the T cell, which can recognize, bind, attack, and kill foreign agents, known as pathogens, that enter the body.
T cells express an incredibly diverse array of receptors that can recognize virtually any pathogen and develop memory against that pathogen to prevent re-infection. Ingeniously, CAR-T therapy engineers the patient’s T cells to recognize surface markers on cancer cells so that they can bind to and kill the tumor.
While there is no doubt that CAR-T therapy has saved countless lives and is one of the most impactful technologies in the hematology/oncology space, there remains room for improvement. In attacking tumor cells, T cells often release inflammatory molecules known as cytokines, an abundance of which can sometimes lead to cytokine release syndrome (CRS).
CRS can manifest in symptoms ranging from fever and headache to serious complications like irregular heartbeat, disorientation, and tremors. Additionally, CAR-T therapy has historically been used to treat blood cancers rather than solid tumors, such as lung, breast, prostate, colon, and bladder cancer.
These hurdles in CAR-T technology pave the way for a promising alternative — CAR-NK therapy. Instead of T cells, CAR-NK therapy harnesses a different type of immune cell known as the natural killer (NK) cell. CAR-NK therapy draws inspiration from CAR-T: rather than T cells, NK cells are genetically modified to target the patient’s tumor cells.
Dr. Louis Weiner, director of Georgetown University’s Lombardi Comprehensive Cancer Center and chair of the Department of Oncology at Georgetown University Medical Center explains that “An NK cell is capable of killing any cell that doesn’t look like it belongs in the body… and it’s been demonstrated for probably 40 years now that our natural killer cells can recognize cancer cells.”
NK cells function similarly to T cells but are instead programmed to kill pathogens nonspecifically. “T cells have a very finely tuned, well orchestrated system for recognizing things that should be eliminated from the body, such as virally infected or bacterially infected cells.” On the other hand, “NK cells are much more broad.”
Yet, the killing mechanisms underlying T cells and NK cells are similar: “These cells will drill a hole into the target, squirt in toxic molecules called granzymes, which cause death of the target cell,” explains Dr. Weiner.
Unique Advantages of CAR-NK
While CAR-T is by far a more well-established and mature technology with an exemplary track record, preliminary evidence suggests that CAR-NK cells may present several advantages over CAR-T.
Firstly, “NK cells don’t make people very sick,” explains Dr. Weiner. CAR-NK cells are less likely to induce cytokine release syndrome and neurotoxicity, as NK cells secrete a different spectrum of cytokines that are less dangerous in large quantities.
Additionally, CAR-T cells have notoriously faced challenges in infiltrating solid tumors, which account for over 90% of new cancer diagnoses.
Dr. Jutatip Panaampon is a research fellow at Dana-Farber Cancer Center who works on immunotherapies for blood cancers like leukemia and lymphoma. She explains that “solid tumors are big and heterogeneous. They are composed of fibroblasts, tumor cells, connective tissues, and more. CAR-T cells cannot infiltrate [the solid tumor] well, or once they infiltrate, they often exhaust or die.”
Preliminary evidence suggests that CAR-NK cells may be better suited for the treatment of solid tumors. This may be due to NK cells being better at infiltrating tumors compared to T cells, which can become nonfunctional when programmed to attack solid tumors.
Moreover, CAR-NK cells are promising candidates for “off-the-shelf” immunotherapies. Given the time and resource-intensive nature of genetically modifying each patients’ immune cells and reinjecting them back into the patient, as is traditionally done in CAR-T, there has been rising demand for T cells obtained from donors or generated from stem cells. Such “off-the-shelf” CAR-T therapies have been an increasingly popular option for patients with advanced disease.
However, as with any transplantation, off-the-shelf immunotherapies pose the risk of rejection by the patient’s body, which can lead to graft vs. host disease. Once again, CAR-NK cells can be used to overcome this obstacle, as “[NK cells] work equivalently to T cells but [are] much less likely to cause graft vs. host disease,” explains Dr. Weiner. Indeed, CAR-NK cell transplantations have shown lower risk of rejection.
The Future of CAR-NK
Given its numerous advantages, CAR-NK therapy has become a hub for innovation in recent years, especially following the rising popularity of immunotherapy for cancer treatment. An early clinical trial for CAR-NK therapy as a treatment option for B cell lymphoma led to remission in 73% of patients.
A follow-up trial at MD Anderson Cancer Center showed that off-the-shelf CAR-NK therapy led to zero cases of cytokine release syndrome, neurotoxicity, or host rejection, demonstrating a remarkable safety profile.
Many researchers are seeking ways to improve the safety and efficacy of CAR-NK therapy, especially with the production of off-the-shelf CAR-NK cells. Dr. Weiner is one of them; his lab is exploring ways to enhance the ability of NK cells to infiltrate and attack solid tumors.
“Our hypothesis is that NK cells are being prevented from getting into solid tumors by these factors [like collagen], and that if we could find ways to overcome these obstacles, that might be helpful,” attests Dr. Weiner.
Ultimately, both Dr. Weiner and Dr. Panaampon hope to eventually elevate CAR-NK therapy as a safe, reliable, and popular treatment option for patients with cancer; one that can rival CAR-T therapy and deliver promising prognoses and remissions in countless patients in the future.
“This is going to be a potentially important component of future solutions to cancer,” predicts Dr. Weiner.
