Engineered Immune Cells and Targeted Antigens Advance Cancer Immunotherapy

Researchers are developing innovative approaches to enhance cancer immunotherapy by engineering immune cells to better target tumors and identifying highly specific antigens for precision treatment. A new study demonstrates that immune cells engineered to sense metabolic by-products secreted by cancer cells can migrate to and infiltrate solid tumors in mice, markedly enhancing survival in models of human breast and ovarian cancers.

The approach equips certain types of immune cells with proteins on their surfaces that can recognize by-products of cancer cells' abnormal metabolism diffusing in the spaces between cells and stimulate the immune cells to migrate toward the tumor. Arming CAR-T cells with specific metabolite-sensing receptors markedly increased the therapies' effectiveness. "We found that when we equip immune cells with receptors that sense metabolites released by cancer cells, they can sense the tumor, migrate toward it, infiltrate it and control tumor growth," noted the senior author of the research, which was published in Nature Immunology.

CAR-T cell therapy has transformed the treatment of several blood cancers since it was first approved by the Food and Drug Administration in 2017 for the treatment of acute lymphoblastic leukemia. But it's been less successful in patients with solid tumors. The thought among the CAR-T research community has been that the CAR-T cells, which are prone to excessive signaling, become exhausted before they can eliminate solid tumors. Additionally, unlike in blood cancers, it is difficult to identify molecular targets on solid tumors that are found only on the cancer cells and not on normal tissue.

In a separate development, researchers have identified two promising therapeutic targets that could reshape the treatment of multiple myeloma. A newly published study in Clinical Lymphoma, Myeloma and Leukemia has confirmed that Kappa Myeloma Antigen and Lambda Myeloma Antigen appear on malignant plasma cells but not on healthy ones, opening the door to treatments that could attack cancer cells with far greater precision while sparing the normal immune system.

Multiple myeloma is the second most common form of blood cancer and remains largely incurable, with most patients eventually experiencing relapse after treatment. Current therapies have improved survival in recent years, but many target proteins that are also expressed on healthy immune cells. This can lead to long-term immune suppression and a higher risk of severe infections.

The study provides evidence that the two antigens are consistently expressed on malignant plasma cells across the entire disease spectrum. Investigators found that the antigens are present from the earliest stages of disease, including the pre-malignant condition known as monoclonal gammopathy of undetermined significance, and become increasingly prominent as myeloma progresses. Their consistent expression and tumour-specific nature make them attractive targets for next-generation immunotherapies, including antibody-based drugs and engineered cell therapies.

Around seventy per cent of myeloma patients have kappa type disease and are therefore likely to express Kappa Myeloma Antigen, while the remaining thirty per cent with lambda type disease are likely to express Lambda Myeloma Antigen. This distribution creates clear targets for immunotherapy programs, several of which are already advancing through clinical development.

An antibody therapy targeting the Kappa Myeloma Antigen is currently advancing in a Phase 2b clinical trial involving patients whose disease has relapsed after treatment with three major classes of myeloma drugs. Earlier clinical studies showed that the antibody did not damage normal immune cells and produced strong responses when used alongside the commonly prescribed myeloma drugs lenalidomide and dexamethasone. A KMA-targeted CAR T cell therapy is also being prepared for a Phase I trial in patients with relapsed or treatment-resistant disease.

Meanwhile, another research team is developing a novel cancer vaccine framework based on messenger RNA technology that promises the ability to create personalized vaccines to treat different types of cancer. To create vaccine candidates, scientists will identify specific mutated tumor proteins called neoantigens, which are unique to each cancer. Neoantigens have the potential to trigger an immune response against cancer, acting like an alarm system that alerts the immune system to the presence of a threat.

After identifying mutations in a tumor, scientists will feed them into an artificial intelligence algorithm to select neoantigen candidates most likely to be effective therapeutic targets. Matching mRNA transcripts will then be created for the selected neoantigens. mRNA carries temporary genetic instructions from DNA that tell cells how to make proteins. T cells in the immune system learn to recognize the resulting neoantigen proteins and attack cancer cells that carry them.

When used in a cancer vaccine, mRNA can be delivered into cells to provide instructions for producing one or more cancer neoantigens, allowing vaccines to be individualized for each patient's tumor. Microscopic fatty bubbles called lipid nanoparticles will be used to deliver the mRNA. Researchers will evaluate neoantigens and vaccine candidates in a mouse model to assess the vaccines' ability to generate an effective immune response against melanoma and to explore their broader therapeutic potential.