People with cancer who respond to immunotherapy drugs have immune cells capable of recognizing and attacking tumors before treatment, according to research from the University of California, Los Angeles (UCLA) published March 23 in the journal Nature . As soon as patients receive immunotherapy, these cells go into action and the cancer remits.
Conversely, if a patient does not have cells capable of attacking the tumor effectively, immunotherapy drugs fail to activate the immune system against cancer. However, the research has revealed that even these patients have some cells capable of recognizing tumor proteins and opens a path of hope for them.
“We can isolate these cells and identify the receptors that recognize the tumor. From there, we can produce more immune cells endowed with these receptors in the laboratory and transfuse them into patients. With this strategy, we hope to be able to increase the percentage of patients who respond to immunotherapy”, explains Cristina Puig-Saus, first author of the research, by videoconference.
Although the work has been based on patients with melanoma, "the strategy can work equally in other types of tumor", points out the researcher.
The treatment has been shown to be safe and has antitumor activity in a phase 1 clinical trial conducted in the United States whose results were presented last November. The clinical trial included not only patients with melanoma but also with colorectal, breast, ovarian or lung cancers.
Of the eleven patients who have participated in the new research now published in Nature, seven have responded to immunotherapy and the treatment has been ineffective in the other four.
The key to the difference between one and the other lies in the so-called neoantigens, which are tumor cell proteins that the immune system can recognize. To recognize them, the T lymphocytes of the immune system develop neoantigen detectors, technically called receptors. Each T cell receptor (or TCR) recognizes a specific part of a neoantigen.
In the seven cases in which immunotherapy has been effective, a large repertoire of lymphocytes equipped with different TCRs has been directed against a few neoantigens. "When tumors present a very clear target, the immune system produces a variety of artillery to attack this target," explains Puig-Saus.
In the four cases in which immunotherapy has been ineffective, the action of lymphocytes against neoantigens has been more diffuse, but not non-existent. The objective of the researchers is to modify the lymphocytes in the laboratory with gene editing so that their action is focused against the neoantigens in which they can be most effective. As has been done in the clinical trial, once the lymphocytes have been modified, they will multiply to have a large number of lymphocytes for each patient.
"Now we can know exactly what each patient's immune system recognizes in their cancer to distinguish it from healthy cells and attack it," says Antoni Ribas, an oncologist at the University of California at Los Angeles (UCLA) and director of the research, in in which the Vall d'Hebron Institute of Oncology (VHIO) participated. "With this very precise knowledge, oncologists who prescribe immunotherapies will be able to understand why their patients respond to treatment," says Ribas.
Since the neoantigens of each patient are different, the treatment must be personalized and it is not yet ready to be applied on a large scale. Right now it takes about six months to develop the therapy for each patient. But if it works - which will have to be demonstrated in future clinical trials - "many steps can be automated and the time needed to produce the therapies will be shortened," says Puig-Saus.
