Researchers from Harvard Medical School and the Massachusetts Institute of Technology (MIT) have made a significant breakthrough in cancer treatment by developing novel 'natural killer' (CAR-NK) cells designed to combat cancer more effectively while simultaneously lowering the risk of severe immune side effects. This innovation addresses critical limitations of existing cellular therapies, offering a promising new avenue for patients.

Natural killer (NK) cells are an integral part of the immune system, capable of identifying and destroying harmful invaders without requiring prior 'training' to recognize specific threats. Similar to CAR-T cells, which have become a cornerstone in certain cancer treatments, CAR-NK cells are genetically engineered to specifically target cancer cells. However, a major challenge with traditional CAR-NK cells has been their potential rejection by the patient's immune system, leading to their rapid depletion and reduced efficacy. The Boston-based research team tackled this by engineering a new series of CAR-NK cells to circumvent this rejection.

The core of their innovation lies in modifying NK cells to 'silence' specific properties that would typically trigger an attack by T cells, another crucial component of the immune system responsible for targeting unfamiliar invaders. Specifically, the researchers found that NK cells could evade detection by T cells if they were modified to not express the surface proteins HLA class 1. These proteins are usually present on NK cells and signal T cells to attack if the immune system perceives them as foreign. By engineering the CAR-NK cells to express short interfering RNA, which stops the genes of HLA 1 from being expressed, they effectively made these cells 'invisible' to the host T cells. Additionally, the CAR modification enabled these cells to produce genes for proteins that enhance their overall effectiveness against cancer.

The efficacy of these modified CAR-NK cells was demonstrated in experiments where mice implanted with cancerous tumors, specifically lymphoma, were injected with the engineered cells. The results were striking: the modified CAR-NK cells persisted in the mice's bodies for three weeks and were able to nearly eliminate the cancer. In stark contrast, mice that received either naturally occurring NK cells or standard CAR-NK cells saw these cells deplete within two weeks, allowing the cancer to spread unchecked. Lymphoma, a type of blood cancer affecting the lymphatic system, impacts approximately 90,000 Americans annually and is responsible for 20,000 deaths.

Beyond improved efficacy and immune evasion, these new CAR-NK cells offer significant safety advantages. The team noted that they were less likely than standard CAR-T cell therapy to cause cytokine release syndrome (CRS), a potentially life-threatening side effect of chemotherapy that can lead to multi-organ failure. Furthermore, the genetic modification process for these enhanced CAR-NK cells required only one additional step. This streamlined approach, as highlighted by Jianzhu Chen, senior study author and professor of biology at MIT, could significantly simplify and accelerate the development of 'off-the-shelf' CAR-NK cells. Such a development would allow these therapies to be readily available for patients immediately upon diagnosis, circumventing the weeks-long development time typically required for traditional CAR-NK and CAR-T cells.

The study, published in the journal Nature Communications, utilized mice with human-like immune systems to model the disease. Researchers are confident that their findings can be adapted for ongoing clinical trials focused on CAR-NK cell therapies for lymphoma and other cancers. The team is also planning to conduct their own clinical trial and is collaborating with a biotech company to explore the potential of CAR-NK cells in treating lupus, an autoimmune disorder affecting 1.5 million Americans, where the immune system mistakenly attacks healthy tissues and organs. Chen summarized the breakthrough, stating, “This enables us to do one-step engineering of CAR-NK cells that can avoid rejection by host T cells and other immune cells. And, they kill cancer cells better and they’re safer.”