Double targeted CAR-T scores in preclinical pancreatic cancer study

Avery
Avery Posey

CAR-T therapies are the hottest property in the oncology R&D field right now, and researchers at the University of Pennsylvania have posted new data showing they can expand its efficacy across a greater range of cancers, while also making treatment safer.   

Chimeric antigen receptor (CAR) T cells are a genetically engineered type of T cell that can target a specific cancer. The tech has been around since the 1990s, but in clinical research terms, it’s still in its infancy.

There are now however CAR-T candidates in the clinic which are showing some stellar results in certain blood cancers, with strong data being posted over the past 12 months from Juno ($JUNO), Kite Pharma ($KITE) and Big Pharma Novartis ($NVS), as well as a number of academic centers (including the University of Pennsylvania, which has a CAR-T development deal with Novartis).

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These are now all in a race to be the first to market and potentially bring in major blockbuster sales.

But there have been some problems--including some serious adverse events across a number of trials--and researchers have not been able to match the impressive data from blood cancers in solid tumors.

The University of Pennsylvania researchers, which include the T-cell research star Dr Carl June, published their findings in the journal Immunity this week, and say they may have found a way to translate the success in leukemias into solid tumors, and potentially reduce the levels of AEs, by using a double target approach.

In a preclinical mouse model, the researchers show how an antibody that recognizes the combination of a known cancer-associated surface protein and a cancer-associated carbohydrate can be applied as a CAR-based therapy for a wide range of solid tumors.

The team, from the University of Pennsylvania's Perelman School of Medicine, showed the CARs’ effectiveness in mouse models of pancreatic cancer.

“We engineered T-cells to target a cancer-associated surface protein with shortened carbohydrate molecules,” said first author Avery Posey, an instructor in pathology and laboratory medicine.

“Future cancer immunotherapies combining the targeting of cancer-specific carbohydrates and cancer proteins may lead to the development of incredibly effective and safe new therapies for patients. These engineered cells will be able to increase cancer specificity of this immunotherapy and decrease the potential for toxicity in patients.”

The researchers developed CAR-T cells that express an antibody which specifically recognizes shortened carbohydrate molecules on a mucin 1 protein.

This protein is usually not on normal cells, but is abundant on the cancer cells of many types of solid tumors and leukemias.

When these CAR-T cells were then injected into mice with leukemia or pancreatic cancer, the tumors shrank--and were even removed entirely in most animals, resulting in increased survival.

The mice with pancreatic cancer were still alive 113 days after treatment with the CAR-T cells. But only one-third of the animals treated with CAR-T cells that did not target the MUCI proteins with the truncated carbohydrate survived until the end of the experiment. 

The researchers also noted that on the safety side, the CAR-T cells could not damage normal human cells or cells without the abnormal carbohydrate.

“These findings suggest that targeting abnormal, cancer-specific carbohydrates on proteins found in normal tissues and solid tumors could become a new immunotherapy for solid cancers,” the authors conclude.

“This combined tumor targeting may lead to future development of safe and effective therapies for patients.” Pancreatic cancer has one of the lowest survival rates, with many being found too late, and few effective treatments on the market to tackle this difficult disease.

University of Pennsylvania is the spiritual home of CAR, given that Dr. June is the professor of pathology and laboratory medicine at the Perelman School of Medicine and director of translational research, and an early innovator in T-cell biology (although not the first inventor of this new type of tech, as first assumed).

The University in fact just last week announced it was to take the lead in a new, first-in-human trial of CRISPR tech, the “cousin of CAR,” which aims to edit certain cancer genes in the hopes of boosting an immune response, while also disabling PD1.

- check out the release
- read the journal article

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