New Co-STAR Receptor Shows Promise in Lab Cancer Study

Using genetic engineering techniques, researchers at the Johns Hopkins University Kimmel Cancer Center and his Ludwig CenterTHE Lustgarten Laboratory And Bloomberg~Kimmel Institute for Cancer Immunotherapy have engineered a new type of cell to recognize and fight cancer.

To make these cells, called Co-stimulatory Synthetic T-cell receptor and Antigen Receptor (Co-STAR) cells, the researchers combined the genetic components of four types of cells that the body normally uses to defend itself against invaders to create a powerful new type of cell: 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 detection device,” recognizing cancer cells as foreign, and the “alarm” triggered by this hybrid detector was reinforced by the MyD88 and C40 components.

In laboratory studies, Co-STARs led to a sustained antitumor response against human cancer cells growing in test tubes and in mice. A description of the work was published July 10 in Scientific translational medicine.

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

However, both TCR and CAR (chimeric antigen receptor, usually using an antibody as a detector), which aim to stimulate an immune response by activating T cells, each have their limitations. Combining the two can overcome these limitations.

“We needed to create a new type of cell because we were trying to target specific antigens called peptide-HLA (human leukocyte antigen) antigens, which are peptide fragments of mutant proteins inside the cancer cell that are displayed on the cell surface by peptide-carrying proteins called HLA,” Mog explains. 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 (genetic variation). This is the most common mutation of the tumor suppressor protein p53, which is in turn the most commonly mutated gene in human cancers.

However, these antigens are present in very small quantities (only one to ten) on a cancer cell, and the classic CAR format would not be able to react to such a small quantity. “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 by additional signaling boosters, so that they can fight cancers more effectively,” explains Mog.

The team had to go through several rounds of engineering to arrive at 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, the Co-STAR cells induced robust and long-lasting proliferation of T cells that could induce deep remissions, and often cure, of human cancer cells growing in mice. In contrast, more conventional T cells, or CAR T cells, were unable to eradicate cancer cells in vitro and only provided temporary tumor control in mice, with the cancers returning a few days later.

“Brian’s results demonstrated that Co-STAR T cells combine the benefits of many of the features of immune cells that normally fight infection in a way that allows them to effectively kill cancer cells in mouse models,” says co-principal investigator Dr. Bert VogelsteinClayton Professor of Oncology, Howard Hughes Medical Institute Investigator and Co-Director of the Ludwig Center. “Co-STAR addresses some, but certainly not all, of the challenges facing T-cell therapies, but certainly deserves further study.”

“I was, honestly, incredibly surprised to see 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,” Mog adds. “Witnessing these cures was a very exciting moment.”

The study’s co-authors were Nikita Marcou, Sarah DiNapoli, Alexander Pearlman, Tushar Nichakawade, Michael Hwang, Jacqueline Douglass, Emily Han-Chung Hsiue, Stephanie Glavaris, Katharine Wright, Maximilian Konig, Suman Paul, Nicolas Wyhs, Jiaxin Ge, Michelle Miller, P. Aitana Azurmendi, Evangeline Watson, Drew Pardoll, Sandra Gabelli, Chetan Bettegowda, Nickolas Papadopoulos, Kenneth Kinzler and Shibin Zhou of Johns Hopkins.

The work was supported by the Virginia and DK Ludwig Fund for Cancer Research, the Lustgarten Foundation, the Commonwealth Fund, Bloomberg Philanthropies, and the Bloomberg~Kimmel Institute for Cancer Immunotherapy, National Institutes of Health (NH) Cancer Center Support Grant P30 CA006973, NIH grants (T32 GM136577, T32 AR048522, 1R21 AI176764, and K08CA270403), the National Institute of General Medical Sciences (grant T32GM148383), the National Cancer Institute (grants T32CA153952 and R37CA230400), and awards from the Leukemia & Lymphoma Society Translational Research Program, the American Society of Hematology, Swim Across America Cancer Translational Research, the Jerome Greene Foundation, the Cupid Foundation, the Stephen and Renee Bisciotti Foundation, the Harrington Scholar-Innovator Fellowship and the Rheumatology Research Foundation.

Johns Hopkins University has filed patent applications related to the technologies described in this article, for which Hsiue, Wright, Douglass, Mog, Hwang, Pearlman, Papadopoulos, Kinzler, Vogelstein, Gabelli, Pardoll, and Zhou are listed as inventors. Vogelstein, Kinzler, and Papadopoulos are founders of Thrive Earlier Detection, an Exact Sciences company (and Kinzler and Papadopoulos are consultants to that company). Vogelstein, Kinzler, Papadopoulos, and Zhou are equity owners in Exact Sciences and are founders or consultants of, and are equity owners in, Clasp Therapeutics, NeoPhore, and Personal Genome Diagnostics. Vogelstein, Kinzler, and Papadopoulos are founders or consultants of, and are equity owners in, Haystack Oncology and Cage Pharma. Papadopoulos is a consultant to Vidium. Vogelstein is a consultant to, and is an equity owner in, Catalio Capital Management. Zhou has a research agreement with BioMed Valley Discoveries. Bettegowda is a consultant to DePuy Synthes, Bionaut Labs, Haystack Oncology, Galectin Therapeutics, and Privo Technologies, and is a co-founder of OrisDX and Belay Diagnostics. Gabelli is a founder and an equity holder of AMS LLC. Konig has received consulting fees from Argenx, Atara Biotherapeutics, Revel Pharmaceuticals, Sana Biotechnology, and Sanofi. Douglass previously consulted for Hemogenyx Pharmaceuticals. Paul consults for Merck, holds an equity interest in Gilead, and has received payments from IQVIA and Curio Science. Pardoll reports grant and patent royalties through Johns Hopkins from BMS, a grant from Compugen, stock in Trieza Therapeutics and Dracen Pharmaceuticals, and founder’s interests in Potenza. He is a consultant for Aduro Biotech, Amgen, AstraZeneca (MedImmune/Amplimmune), Bayer, DNAtrix, Dynavax Technologies, Ervaxx, FLX Bio, Rock Springs Capital, Janssen, Merck, Tizona, and Immunomic Therapeutics. Pardoll also serves on the scientific advisory boards of Five Prime Therapeutics, Camden Nexus II, and WindMIL and on the board of directors of Dracen Pharmaceuticals. Wright and Gabelli are current or former employees of Merck Sharp & Dohme and may hold stock or stock options. The companies named above, as well as others, have licensed previously described technologies related to the work described in this article from The Johns Hopkins University. Vogelstein, Kinzler, and Papadopoulos are inventors of some of these technologies. The licenses for these technologies are or will be associated with stock or royalty payments to the inventors and to The Johns Hopkins University. Patent applications for work described in this article may be filed with The Johns Hopkins University. The terms of all such agreements are managed by The Johns Hopkins University in accordance with its conflict of interest policies.