By Arra Ju ’27
Currently, in your body, cells are committing cannibalism.
More commonly known as killer T-cells, these cells that commit “cellular cannibalism” exist in our body and carry out an immune response via this natural process of killing foreign cells, cancer cells, and cells infected with a virus. The surfaces of T-cells are covered by many T-cell receptors that can only bind to a specifically shaped molecule, known as an antigen. Once the T-cell receptor fits with its respective antigen on the surface of another cell, the killer T-cell knows to release cytotoxins to kill the cell.
Scientists have discovered the value of this natural mechanism, and novel cancer therapies have been developed to leverage this process, such as chimeric antigen receptor (CAR) T-cell immunotherapy. CAR T-cell therapy involves genetically engineering a patient’s T-cells to express chimeric antigen receptors (CARs) that target specific proteins (antigens) on cancer cells. The modified CAR T-cells are amplified in the lab and then infused back into the patient to attack the cancer. CAR T-cell therapies have shown remarkable efficacy in treating certain blood cancers like leukemia and lymphoma. However, developing effective CAR T-cells for solid tumors has been more challenging. Solid tumors, like breast and colon cancer, express different antigens on their cell surface–including antigens often found on healthy cells. Therefore, the identification of consistent and safe targets that are uniformly expressed on such cells has limited the application of CAR T-cell therapy to solid tumors.
Schematic demonstrating the ProCAR platform, in which synthetic tags are produced and released by tumor-colonizing probiotic bacteria to label ubiquitous components of solid tumors for lysis. Adapted from Vincent et al. (2023)
In a recent study, synthetic biologists from Columbia University have answered this million-dollar question by developing a groundbreaking strategy to attack tumors. Tal Danino, associate professor of biomedical engineering at Columbia Engineering, led the study published by Science where they harnessed the tumor-targeting abilities of engineered bacteria (tumor colonizing probiotic bacteria).1
Found in certain species of bacteria, the tumor-targeting mechanism works by selectively colonizing immune-privileged tumor cores, different from CAR T-cells which require significant engineering to target and infiltrate solid tumors; immune-privileged tumor cores are the regions within tumors that have developed mechanisms to evade and suppress the immune system. These bacteria can grow within hostile hypoxic (low levels of oxygen) and necrotic (death in a localized area of living tissue) tumor microenvironments. Using these advantages, Danino and his team programmed these “tumor-seeking” bacteria to colonize the tumor cores and release synthetic targets that label tumor tissue–essentially painting the solid tumors with a synthetic tag recognizable by the CAR T-cells. Unlike traditional CAR T-cell therapies where natural tumor antigens were targeted, Danino explored the implementation of synthetic antigens. Their strategy to combine the advantages of CAR T-cell therapy and tumor-colonizing probiotic bacteria ensures the safe and systematic delivery of synthetic antigens to solid tumors and, subsequently, the specific targeting and lysis of tumor cells on-site.
The experimentation primarily focused on two steps: 1) engineering the probiotics to deliver synthetic antigens to the tumor microenvironment for “tagging” and 2) programming CAR T-cells to recognize the “tags.” A well-characterized non-pathogenic probiotic strain of Escherichia coli was engineered with a synchronized lysis circuit (SLIC) integrated into its genome. This SLIC allows for the controlled delivery of synthetic CAR targets directly to the tumor core, regulated by quorum sensing. As the bacteria grow and reach a critical population density within the solid tumor microenvironment (TME), they trigger lysis events that cyclically release genetically encoded payloads on site, enhancing targeted therapy within the tumor. The researchers then conducted killing assays using ProCAR T-cells provided with Tags, which showed dose-dependent cytotoxicity against target cancer cells, with significant lysis even at low effector-to-target (E:T) ratios. Cell surface interaction studies demonstrated that Tags effectively coat the surface of cancer cells but do not bind to rested or activated T cells, indicating specific targeting of tumor cells by Tags. The engineered CAR T-cells displayed antitumor behavior through confocal microscopy images, showing the clustering of CAR receptors at the interface between T-cells and cancer cells after exposure to Tags. This indicated effective synapse formation and CAR T-cell activation upon binding to Tags.
The Danino Lab team continued beyond just developing a probiotic-guided CAR T-cell (ProCAR) platform. The study showed that the multifunctional probiotics were engineered to co-release chemokines (small secreted proteins that stimulate the migration and positioning of immune cells in tissues) that enhance CAR T-cell recruitment and therapeutic response, improving the platform’s efficacy. The platform performed promisingly, exhibiting safe and effective behavior in multiple xenografts and syngeneic models of human and mouse cancers.
Thus, a universal CAR T-cell and universal antigen have been born. But what does this mean for the field of cancer treatment?
Solid tumors, such as those found in breast, lung, and colorectal cancers, account for the majority of cancer-related deaths worldwide. Danino Lab’s ProCAR platform is poised to revolutionize the treatment of solid tumors. The universal CAR T-cell attacks the universal antigen; this platform may treat any solid tumor type without identifying a specific tumor antigen. Custom CAR T-cell products for distinct cancer types and different patients will no longer be necessary. By enabling the treatment of a wider range of solid tumors, the ProCAR platform could significantly expand the number of patients who can benefit from CAR T-cell therapy. Time and treatment accessibility, two crucial factors in a cancer patient’s prognosis, are saved by the versatile nature of this advanced immunotherapy platform.
The development of the ProCAR platform represents a major milestone in the ongoing quest to harness the immune system to fight cancer. By engineering bacteria to guide CAR T-cells specifically to solid tumors, this approach offers new hope for patients with advanced cancers who have exhausted other treatment options. As research in this area continues to progress, we can look forward to a future where precision-guided immunotherapies become a mainstay of cancer treatment, bringing us closer to the ultimate goal of conquering this devastating disease.
Arra Ju ’27 is a staff writer at The Princeton Medical Review. She can be reached at aj5591@princeton.edu.
References:
- Vincent, R. L., Gurbatri, C. R., Li, F., Vardoshvili, A., Coker, C., Im, J., Ballister, E. R., Rouanne, M., Savage, T., de los Santos-Alexis, K., Redenti, A., Brockmann, L., Komaranchath, M., Arpaia, N., & Danino, T. (2023). Probiotic-guided CAR-T cells for solid tumor targeting. Science, 382(6667), 211–218. https://doi.org/10.1126/science.add7034
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