Building A Better Blend of Tumor-Fighting Cells

Technion researchers have developed a technique that could produce a more effective blend of tumor-fighting immune cells used to treat cancers such as metastatic melanoma.

Prof Reiter  Prof. Yoram Reiter

By delving deeper into the underlying properties of these cell blends, called tumor-infiltrating lymphocytes or TILs, Prof. Yoram Reiter of the Technion-Israel Institute of Technology, his Ph.D. student Kfir Oved and colleagues have found a way to predict which TILs pack the strongest anti-tumor punch.

With this knowledge, the researchers were able to turn weaker TILs into potent tumor fighters, Reiter and fellow researchers Jacob Schachter and Michal Besser at the Ella Institute for Melanoma Research and Treatment report in the journal Molecular Systems Biology.

The accomplishment, highlighted in the May 1st issue of Science magazine, is “hopefully a step toward less toxic tumor therapy” in humans, said Science deputy editor Barbara Jasny.

While the technique was tested on TILs from melanomas, Reiter said the study’s findings could shed light on “many biological events and disorders in which combinations of cells play a role,” from immune diseases to tissue engineering.

TILs are used in a clinical procedure called adoptive cell transfer, where they are removed from a metastatic melanoma patient’s tumor and evaluated for their anti-tumor activity. TILs that show the strongest anti-tumor response are coaxed to multiply and then re-injected back into the patient.

But the procedure is done without answering an important question: what makes some TILs better tumor fighters than other TILs? Within the complicated mix of interacting and differing cells in a TIL, is there a “secret ingredient” that determines whether a TIL will react strongly or weakly to a tumor?

Reiter and colleagues decided to answer this question by looking closely at the characteristics of the immune cells within 91 TILs removed from 27 melanoma patients. They discovered that the TILs contained several different “subpopulations” of immune cells, with each subpopulation distinguished by a particular set of chemical markers on the cell surfaces.

The researchers found no secret ingredient, and no single subpopulation that made a TIL reactive against tumors. But with computational modeling, they devised a set of rules to predict which TILs would show the most anti-tumor activity based on their particular combination of subpopulations.

“The computational tools we developed allowed us to predict whether a TIL culture will respond to the tumor with an accuracy of more than 90%,” said Reiter.

Guided by these rules, the researchers decided to try building a better TIL by altering its mix of subpopulations. “This enabled us to turn nonreactive TILs into reactive ones and vice versa,” Reiter said.

The results were dramatic: in 12 non-reactive TILs taken from four patients, the researchers obtained a 106-fold increase in TIL anti-tumor activity, by introducing an optimal blend of subpopulations within the TIL.

While the findings are promising, the technique needs further testing before it can be used in clinical trials. “We need to expand the samples that we have tested from more patients, followed by more examples on TIL cultures that can be transformed from non-reactive to reactive,” explained Reiter, who said he hopes to collaborate with leading centers in the United States on such studies.

The Technion-Israel Institute of Technology is Israel's leading science and technology university.  Home to the country’s winners of the Nobel Prize in science, it commands a worldwide reputation for its pioneering work in nanotechnology, computer science, biotechnology, water-resource management, materials engineering, aerospace and medicine.  The majority of the founders and managers of Israel's high-tech companies are alumni. Based in New York City, the American Technion Society (ATS) is the leading American organization supporting higher education in Israel, with offices around the country.


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