Immunotherapy: what future for this therapeutic revolution?

Immunotherapy does not target the tumor directly. It mainly acts on the patient’s immune system to make it able to attack cancer cells. It is based on monoclonal antibodies, in particular checkpoint inhibitors (anti-PD-1, anti-PD-L1, anti-CTLA-4), bispecific antibodies, adoptive transfer of cells (Car-T cells) or further tumor vaccination.

Patients in complete remission

Anti-cancer immunotherapy is a real breakthrough therapeutic innovation. These treatments have achieved long-lasting remissions in cancers such as metastatic melanoma. “For 15 years now, we have had 5-year data with patients in complete remission”, welcomes Gérard Zalcman, Professor of pulmonology, thoracic oncologist and specialist in lung cancer.

“We can of course also speak of thoracic cancers, for which immunotherapy now has indications in practically all forms”, continues the expert. Gérard Zalcman details: “concerning non-small cell lung cancer (NSCLC), immunotherapy has given very spectacular long-term survival results, with almost complete remissions at three years, which had never been seen with the only About small cell lung cancers (SCLC), for which the same chemotherapy was given for 30 years, the advent of immunotherapy has made it possible to improve things, by increasing long-term survival in the forms Finally, for mesothelioma (a chest tumour), immunotherapy has been a major advance, with a very significant and spectacular improvement in survival compared to chemotherapy.”

Immunotherapy is not reserved for the sole treatment of cancer. It is also used to stimulate the immune system against various infectious agents, especially in patients whose immunity is weakened (HIV, patients after chemotherapy or radiotherapy). It can also be used to treat immune system imbalances in diseases such as lupus, rheumatoid arthritis, multiple sclerosis… The objective is to block immune responses in addition to conventional immunosuppressive treatments.

Tomorrow’s challenges

Thereby, “Immunotherapy will surely be one of the most used therapies in the years to come”, analyzes Gérard Zalcman, before adding: “but there is still a lot of progress to be made in this area, because it is not a miracle treatment, it should not be oversold”.

In particular, what remains to be determined is what drives the response to a particular immunotherapy treatment in a given patient. Indeed, apart from melanoma or Hodgkin’s lymphoma, where the response rates are high (40% and 60% respectively), the percentage of patients responding to these immunotherapies as monotherapy is generally around 15%. One of the current challenges is therefore to identify the biomarkers associated with the response, to avoid unnecessarily exposing patients, but above all to understand the mechanisms of resistance in order to adapt the therapeutic strategy.

“That’s tomorrow’s challenge. The big problem is that we don’t have absolutely effective predictive biomarkers, far from it. We have things that are relatively imperfect, such as the expression of the protein against which are directed most immunotherapies, which we call “PD-L1”. We can have negative PD-L1 on the tumor and therefore very good responses, and conversely we have inefficiencies observed even though there is a strong expression of PD-L1″, explains the thoracic oncologist. “The mutational load was also a big disappointment in terms of prediction, and gene expression signatures are still under research. In the lung, we know that it is the less rapidly evolving tumors that can benefit the plus immunotherapy as monotherapy”.

The international multicenter phase 2 clinical trial called Keynote-158, the first results of which have just been published in the Lancet Oncology, also contributes to defining a new biomarker, relevant for determining the patients likely to benefit from treatment with pembrolizumab, an anti-PD-1 immunotherapy. “The hypothesis, which has not been formally demonstrated in the clinic, is that the more mutations there are in the tumor genome, the more the tumor cell produces abnormal proteins, likely to be recognized by the patient’s immune system. “, explains Aurélien Marabelle, clinical director of Gustave Roussy’s immunotherapy program.

Moreover, the response to a single immunotherapy treatment (monotherapy) is sometimes atypical and is not always easy to assess according to the usual criteria for evaluating the response to a treatment. Thus, even in the event of non-response, the treatment can still bring a benefit to the patient. The response may also be delayed and the tumor may regress long after the start of treatment or even after stopping treatment. Finally, in other cases, there seems to be no response, but when the patient receives another treatment – ​​chemotherapy for example – the response to it is greatly increased. “It is a question of better apprehending these mechanisms”, explains Leem.

Adverse effects

Finally, these new immunotherapy approaches are not devoid of toxicities linked to the activity of the immune system, high or excessive, which can lead to autoimmune reactions (i.e. the immune system attacks its own cells that he recognizes as being foreign to the organism). In the future, “better control of these toxicities will be essential”, continues the Leem.

Gérard Zalcman concludes: “As with all effective drugs, there are side effects, even if there are 50% fewer side effects compared to chemotherapy. There are mainly effects on the level of thyroid hormones, inflammation at the level of the colon which gives diarrhea, and finally lung inflammation. All organs can be affected, but this only concerns 1 to 5% of patients treated at the most.”

Subject made from the LEEM file “100 questions about medicine”.

Find below the LEEM sheets on the themes “Immunotherapy, the new frontier?“:

https://www.leem.org/100-questions/immunotherapie-la-nouvelle-frontiere