Dec 08, 2021
JERUSALEM WEATHER

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Cancers have to be regarded as unique to each patient, but if there were a way to identify features common to many malignant tumors, it could save time and be used to develop effective immunotherapy for whole groups of patients. 

Immunotherapy – the prevention or treatment of cancer and other diseases with substances that stimulate the immune respons – is an anti-cancer weapon that has been added in recent years to surgery, chemotherapy and radiation. It has sparked new hope for oncology patients, but for it to work, the patient’s immune system must be able to “see” the tumor. There are ways of enhancing this recognition in individual cases, but such solutions are, by definition, personalized –which greatly limits their use.

Prof. Yardena Samuels and her doctoral student Dr. Aviyah Peri of the Weizmann Institute of Science in Rehovot, together with their colleagues, have now developed a method for identifying cancer “hotspots.” These are features common to many tumors and can therefore be used to develop effective immunotherapy for entire groups of patients. 

The researchers have already used the method to identify a hotspot characteristic of a particularly aggressive form of melanoma in one major subset of patients. The study has just been published in the Journal of Clinical Investigation.

These hotspots are physical structures on cancer cells’ outer membranes that can provide the immune systems of multiple patients with “access” to a tumor. These molecular structures contain mutated peptides called neoantigens that the immune system’s T cells recognize as foreign – the first step in binding to the neoantigens and killing the cancerous cells. 

In fact, this T-cell action is the ultimate goal of all types of immunotherapy, so scientists have been using neoantigens to prime T cells for a successful attack. But since most neoantigens result from unique mutations characteristic of individual tumors, when a particular neoantigen is used to activate a patient’s T cells, the same therapy cannot be applied to other patients. 

Only a handful of neoantigens – those derived from recurrent mutations appearing in numerous patients – qualify as “hotspots,” but these are hard to find. Part of the difficulty comes from the fact that the neoantigens on the cellular membranes are presented to the immune system by protein complexes called HLA, and these complexes come in thousands of versions, so together with the cancerous mutations, there can be millions of individual variations. 

Because of this enormous variability, “hotspot” neoantigens have until now been found mostly by luck. In the new study, a team headed by cell biologist Samuels has developed a method for identifying these cancer hotspots in a systematic manner. Referred to as a “data-driven approach to identifying recurrent neoantigens,” it involves bioinformatics followed by lab analysis. Peri led the study, conducted in the Samuels lab with the late Prof. Nir Friedman of Weizmann’s immunology department, Prof. Masha Niv of the Hebrew University of Jerusalem (HUJI), Prof. Steven A. Rosenberg of the US National Cancer Institute, Prof. Cyrille Cohen of Bar-Ilan University in Ramat Gan (near Tel Aviv), Dr. Ansuman Satpathy of the Stanford University School of Medicine and other researchers.

As the first step, the scientists applied algorithms to search through international databases containing information on the genomes of thousands of cancer patients. Focusing on the most serious type of skin cancer, melanoma, they surveyed oncogenes, looking for common mutations presented by common forms of HLA. The team’s search produced a number of neoantigens that could potentially be considered “hotspots.” Next, the scientists subjected these candidate molecules to laboratory analysis known as HLA peptidomics, in which they isolated the mutant peptides from the HLA complexes and investigated their interactions with T cells. 

Using this approach, the scientists identified a “hotspot” neoantigen derived from an oncogene known as RAS, which is involved in causing a third of all human cancers. This neoantigen, belonging to a form of RAS that causes a particularly aggressive form of melanoma, appears in some 20 percent of melanoma cases. In collaboration with Friedman and Satpathy, the scientists isolated the T-cell receptor that can recognize this “hotspot” neoantigen in melanoma tumors. 

They then engineered T cells from healthy individuals to express this receptor and incubated them in a test tube with tumor samples from patients whose tumors displayed this hotspot. The T cells were activated by the neoantigen, killing the tumor cells in a highly specific manner – that is, only those cells that displayed the neoantigen.

“We’ve uncovered a neoantigen that is expressed in thousands of new melanoma cases every year, and we’ve shown that it can be used in these patients to mark tumor cells for immune destruction,” Peri asserted.

“Our study suggests that our newly developed platform can lead to ‘off-the-shelf’ immunotherapies in which T-cell receptors that recognize cancer hotspots can be prepared in advance, ready to be applied in groups of patients whose tumors have been shown to harbor these hotspots,” added Samuels. Such treatments would be easier and cheaper than tailoring personalized T cells to each new patient. 

Yet another major advantage of this approach is that it makes use of “hotspot” neoantigens derived from oncogenes. When an oncogene like RAS is active in a tumor, it is expressed in all tumor cells. This means that the “hotspot” immunotherapy is more likely to wipe out the entire tumor, rather than only parts of it, as was the case with therapies that targeted neoantigens present in only some of the tumor cells. 

“Our novel approach could make it possible to apply personalized treatments on a larger scale than today,” Samuels concluded. “It is ready to be developed for use in hospitals, and it can be applied to a variety of cancers, not only melanoma.” 

The Yeda Research and Development Company, the Weizmann Institute’s technology transfer arm, is currently seeking to promote the method’s development for clinical use, through a company that is being established to this end.