A new anticancer immunotherapy using chimeric antigen receptor (CAR) T-cells has been developed that targets tumors as well as blood-borne cancer cells. Still in clinical development, it exhibits no toxicity and extremely tight targeting. If this therapy develops as expected, it could be a ground-breaking development for oncologists everywhere.
The therapy, developed at the University of Pennsylvania (UoP) lab of Carl June, MD, is the first to target the carbohydrates of glycoproteins by CAR-T cells. Dubbed glycoCARs, “this approach allows us to target solid tumors for first time with engineered T cells that don’t pose any toxicity to normal tissue,” noted first author Avery Posey, Jr., PhD. “This is revolutionary.
“Currently, adoptive immunotherapy uses patients’ own cells to target cancer. That’s very effective in refractory pediatric and adult leukemia. In pediatric patients, 93 percent went into remission after treatment, even after failing other cancer therapies,” Dr. Posey said.
As he explained, “The T cells target the CD19 protein on the surface of leukemia cells. That marker also is on the surface of normal B cells. Therefore, both normal and leukemia cells are eradicated.
The resulting B cell lymphopenia can be overcome by gamma-globulin supplementation. It’s a tolerable condition,” he said. That approach is viable for leukemia and probably other hemopoietic diseases.
“The approach of targeting proteins shared between normal tissues and cancer, however, doesn’t work well for targeting solid tumors, particularly those of the kidney, liver, lung or other vital organs,” he continued.
Some of these engineered T cell therapies have unexpectedly targeted normal tissue within vital organs, triggering serious adverse events, including death. “Realizing that, other research groups have designed suicide systems, transiently expressed the CAR-T cells or established other mechanisms to improve the safety profile of their therapeutic.
Targeting solved with glycosylation
“Our approach adds a layer of complexity that appreciates cancer-specific glycosylation,” Posey said. The CAR-T cells use the 5E5 monoclonal antibody to target a specific surface protein (MUC-1) that has shortened carbohydrate molecules on the surface of cells so, “although normal cells have the same glycoprotein on their surface, the carbohydrates look different.” Consequently, only cancer cells are targeted.
To test that design, “we took normal and abnormal glycosylated cells and put them in a test tube with cancer-specific glycoCAR-T cells. The CAR-T cells killed only the abnormal cells. There was no bystander effect,” Posey said. In subsequent studies, mice treated with this glycoCAR therapy survived 113 days after treatment, while two-thirds of those treated with control, nonspecific CAR-T cells perished before the experiment concluded.
The penetration of T cell therapies like these into solid tumors hasn’t been addressed yet in this work. That is a challenge throughout immunotherapy and will be addressed in the future. The ultimate goal is to develop highly specific and effective cancer therapeutics with dramatically less toxicity.
Dr. Posey said he foresees no challenges in transferring this work from the preclinical stage to the clinic. “We’re currently evaluating cancer types to determine the best histotype for clinical trials,” he said. The research group also is considering filing an IND, which, if filed soon, would allow clinical trials to begin in about one year.
Currently, Posey is creating additional glycoCARs in his own laboratory that can address more universal cancer targets. “We presume the CAR described wouldn’t target liver cancers, for example, because it doesn’t target the MUC-1 glycoprotein. We have recently made new glycoCARs that potentially have broader anti-tumor activity and are evaluating them now for efficacy,” Posey said. The 5E5 glycoCAR targets two O-linked hypoglycosylated epitopes on MUC-1. Details were outlined in the June 2016 issue of Immunity.
Posey is collaborating with researchers at the University of Copenhagen, who are developing new methods for targeting glycoproteins and other glycosylations. Copenhagen researchers also are co-founders of GO Therapeutics, an innovative biotech company focused around increasing the tumor specificity of immunotherapy using the glycoproteome. “GO is developing cancer-specific antibodies that would be great to evaluate as glycoCARs,” Posey said. The University of Pennsylvania has a licensing agreement with Novartis to study and commercialize CAR-T cells. Also, Dr. Posey and Dr. June are members of the Parker Institute for Cancer Immunotherapy, which supports the University of Pennsylvania’s cancer immunotherapy program.
“GlycoCARs represent a novel approach to cancer immunotherapy that hasn’t been attempted anywhere else,” Posey said. “We are interested in pursuing discussions with potential partners for new glycosylation-specific cancer therapeutics.”
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