Study Shows New Co-Star Receptor to be Promising in Cancer Treatment

T-cell therapies such as engineered T-cell receptors or TCRs and Chimeric Antigen Receptors (CARs) T-Cell have, with a doubt, revolutionized the health outcomes for patients diagnosed with certain subsets of B cell leukemia or lymphoma, while, at the same time offer durable clinical responses.[1]

However, there are numerous challenges that limit the therapeutic efficacy of CAR T-cells in the treatment of solid tumors and hematological malignancies. Among the barriers to of these therapies are severe life-threatening toxicities, possible side effects such as cytokine release syndrome, modest anti-tumor activity, antigen escape, restricted trafficking, and limited tumor infiltration.

At the same time, while engineered T-cell receptors (TCR T-cell) have shown encouraging results in the treatment of solid tumors, including cancers responding poorly to current immunotherapies, such as sarcomas, the complexity of this therapeutic strategy remains associated with many challenges.[2]

Overcoming challenging drawbacks
To overcome these drawbacks, research teams at the Johns Hopkins Kimmel Cancer Center and its Ludwig Center, the Lustgarten Laboratory and Bloomberg~Kimmel Institute for Cancer Immunotherapy used genetic engineering techniques to designed a novel type of high-affinity antibody–expressing T-cells that can recognize and fight cancer.

To produce the cells, called Co-stimulatory Synthetic T-cell receptor and Antigen Receptor or Co-STAR cells, the scientists combined genetic components of four types of cells that the body normally uses to defend against invaders to make a powerful new cell type: T-cell receptors (TCRs) from T cells, antibodies from B cells, MyD88 from white blood cells called monocytes, and CD40 from dendritic and other cells.

The TCR and antibody components served as an invader detecting device, recognizing cancer cells as foreign, and the alarm triggered by this hybrid detector was boosted by the MyD88 and C40 components.

In laboratory studies, Co-STARs led to a sustained anti-tumor response against human cancer cells growing in test tubes and in mice. A description of the work was published July 10, 2024 in Science Translational Medicine.[3]

Most promising
T cell-based therapies are among the most promising approaches to treat advanced cancer and are the subject of intense research, explained lead study author Brian Mog, M.D., Ph.D., an internal medicine resident at Brigham and Women’s Hospital in Boston. He was a medical and graduate student at the Johns Hopkins University School of Medicine when the research was conducted.

However, both TCR and CAR (usually using antibody as the detector), which are aimed at stimulating an immune response by activating T-cells, have limits. The new study shows that the combination of the two can overcome these limitations.

“We needed to make a new type of cell, because we were trying to target specific antigens called peptide-HLA (human leukocyte antigen) antigens, which are peptide fragments from mutant proteins inside the cancer cell that are displayed on the cell surface by peptide-holding proteins called HLAs,” Mog explained.

Their specific target was a peptide containing the R175H mutation of p53 (the 175th amino acid of p53 is mutated from arginine to histidine), displayed on the HLA-A2 allele (gene variation). This is the most common mutation in the tumor suppressor protein p53, which is in turn the most commonly mutated gene in human cancers.

However, these antigens are present at very low numbers (just one to 10) on a cancer cell, and the classic CAR format would not be able to react to such a small amount.

Combining advantages
“Our goal was to combine some of the advantages of the CAR format with those of the natural T cell receptor on T cells, supplemented with additional signaling boosters, so that they could fight cancers more effectively,” Mog noted.

The team went through multiple rounds of engineering to come up with the final design, testing their receptors in model cancer cell lines in test tubes and then in mouse models of cancer. The final Co-STAR T-cells were able to continuously kill human cancer cells in test tubes.

When tested in mouse models of cancer, Co-STARs induced a robust, long-lasting proliferation of T-cells that were able to induce profound remissions, and often cure, human cancer cells growing in mice. By contrast, more conventional T-cells or CAR T-cells were not able to eradicate the cancer cells in vitro and only brought about temporary tumor control in mice, with the cancers re-emerging days later.

“Brian’s results demonstrated that Co-STAR T-cells combine the advantages of many features of immune cells that normally fight infection in a way that allowed them to effectively kill cancer cells in mouse models,” says co-senior investigator Bert Vogelstein, M.D., Clayton Professor of Oncology, Howard Hughes Medical Institute investigator and co-director of the Ludwig Center.

“Co-STARs address some, but certainly not all, challenges confronting T cell-based therapeutics but are certainly worthy of continued investigation,” Vogelstein added.

“I was, honestly, incredibly surprised that the Co-STARs worked so well in mice, given that I had generated so many different types of T cells over four years that could only slow the growth of cancers in mice” adds Mog.

“Witnessing those cures was a very exciting moment,” Mog concluded.

References
[1] June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science. 2018 Mar 23;359(6382):1361-1365. doi: 10.1126/science.aar6711. PMID: 29567707.
[2] Baulu E, Gardet C, Chuvin N, Depil S. TCR-engineered T cell therapy in solid tumors: State of the art and perspectives. Sci Adv. 2023 Feb 15;9(7):eadf3700. doi: 10.1126/sciadv.adf3700. Epub 2023 Feb 15. PMID: 36791198; PMCID: PMC9931212.
[3] Mog BJ, Marcou N, DiNapoli SR, Pearlman AH, Nichakawade TD, Hwang MS, Douglass J, Hsiue EH, Glavaris S, Wright KM, Konig MF, Paul S, Wyhs N, Ge J, Miller MS, Azurmendi P, Watson E, Pardoll DM, Gabelli SB, Bettegowda C, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S. Preclinical studies show that Co-STARs combine the advantages of chimeric antigen and T cell receptors for the treatment of tumors with low antigen densities. Sci Transl Med. 2024 Jul 10;16(755):eadg7123. doi: 10.1126/scitranslmed.adg7123. Epub 2024 Jul 10. PMID: 38985855.

Image: New cell type, called Co-STAR, fights cancer cells. Photo courtesy: © 2024 Elizabeth Cook. Used with permission.

Featured image courtesy: CDC on Unsplash. Used with permission

DOI:10.14229/onco.2024.07.10.001