People with cancer who respond to immunotherapy drugs have immune cells capable of recognizing and attacking tumors even before treatment, according to research from the University of California, Los Angeles (UCLA) published on 23 March in the journal Nature. When patients receive immunotherapy, these cells spring into action and the cancer goes into remission.
On the other hand, if a patient does not have cells capable of attacking the tumor effectively, immunotherapy drugs fail to activate the immune system against cancer. However, 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 equipped 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, via video conference.
Although the work was based on patients with melanoma, “the strategy can work equally well in other types of tumor”, the researcher points out.
The treatment has been shown to be safe and has antitumor activity in a phase 1 clinical trial in the United States, the results of which were presented in November. The clinical trial involved not only patients with melanoma but also with colorectal, breast, ovarian or lung cancers.
Of the eleven patients who took part in the new research published now in Nature , seven have responded to immunotherapy and the treatment has been ineffective in the other four.
The key to the difference between them and others lies in the so-called neoantigens, which are proteins from tumor cells that the immune system can recognize. To recognize them, the T lymphocytes of the immune system develop neoantigen detectors, technically called receptors. Each T lymphocyte receptor (or TCR, by its initials in English) recognizes a specific part of a neoantigen.
In the seven cases where immunotherapy has been effective, a broad repertoire of lymphocytes equipped with different TCRs has been directed against a small number of 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 aim of the researchers is to modify the lymphocytes in the laboratory with genetic editing so that their action is focused against the neoantigens in which they can be more 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, oncologist at the University of California at Los Angeles (UCLA) and director of the research, in which the Institute of Oncology of Vall d’Hebron (VHIO) has participated. “With this precise knowledge, oncologists who prescribe immunotherapies will be able to understand why their patients respond to treatment,” says Ribas.
Since each patient’s neoantigens are different, treatment must be personalized and cannot yet be applied on a large scale. It currently takes about six months to develop the therapy for each patient. But if it works – which will have to be demonstrated in upcoming clinical trials – “many steps can be automated and the time needed to produce the therapies will be shortened”, declares Puig-Saus.
