Department of Senological, Gynecological, Plastic and Reconstructive Surgery - Paris Professor Fabrice Lecuru - Institut Curie
  • Ovarian cancer - cancer immunotherapy

    Cancer immunotherapy

    Chapter written by Pr JE Kurtz, Department of Medical Oncology, University Hospitals of Strasbourg, 1 Av Molière 67098 Strasbourg



    “Modern” cancer immunotherapy is based on the work of the two 2018 Nobel Prize winners for medicine, James Allison and Tasuku Honjo, for their discovery of immune system checkpoints. To understand how immune system checkpoint inhibitors work, you need to have some knowledge of immunology.

    1) Our immune system is trained to recognize antigens "outside" the body
    2) Our immune system must recognize our own antigens so as not to attack them
    3) The cells of our body present their antigens via MHC proteins or major histocompatibility complex, which are class I or II HLA molecules
    4) Some cancers have more mutations than others, and thereby present new antigens (aka neo-antigens) to the immune system. Not all mutations are equal for this, but for the sake of understanding, it will be agreed that the more mutations there are, the more neo-antigens there are, and the more likely the tumor will respond to immunotherapy.
    < br> The bases of cancer immunotherapy are therefore based on two crucial steps in the activation of the T immune response (mediated by T cells):
    i) A first step where the T lymphocytes will be activated by the dendritic cells (of the macrophage family) which “show” them a tumor antigen via the MHC molecules. This positive stimulatory action is nevertheless regulated by an opposite, inhibitory action, mediated by the contact between a molecule of the T lymphocyte called CTLA4 and its partner CD80 located on the antigen-presenting cell. This system is therefore in equilibrium, due to the co-existence of opposing actions. Nevertheless, this balance maintains the lymphocyte in a state of insufficient activity to trigger effective antitumor action.
    ii) The second stage takes place in the tumour. The activated T lymphocytes will migrate towards the latter, via the lymphatic or hematogenous route and infiltrate the tumor tissues. They will be able to recognize the tumor antigens for which they have been “educated” via their “T-cell receptor” (or TCR) and trigger a cytotoxic action. However, there is also an inhibitory action here because the tumor cell will express a molecule (PDL-1) which will recognize its partner on the T lymphocyte (PD1). The PD1/PDL1 interaction will exert an inhibitory action on the T lymphocyte, counterbalancing the TCR-mediated activation. We are witnessing the extinction of a cytotoxic response which results in an exhaustion of the T lymphocytes, which have become incapable of triggering a cytotoxic action.

    In total, the inefficiency of the immune system in the fight against cancer can be based on several notions:
    1) The absence of antigenicity of tumors which present few mutations (low mutational load) and which will not respond to immunotherapy, for lack of neo-antigens
    2) The absence of lymphocyte infiltrate in the tumor (“cold” or “excluded” tumours)
    3) An inadequate balance between stimulation and inhibition of T lymphocytes in their activation by the dendritic cell by the CTLA4/CD80 interaction
    4) An extinction of the cytotoxic response in the tumor mediated by the PD1/PDL-1 interaction

    In 2018, cancer immunotherapy is based on a pharmacological action which aims to restore an effective balance at the level of the two checkpoints of the immune system. It is therefore easy to understand that this therapeutic action aims to interfere with the interactions between CTLA4 and CD80 on the one hand, as well as PD1 and PDL-1 on the other hand.

    In the first case, the administration of an anti-CTLA4 monoclonal antibody (by IV route) will displace CD80 from CTLA4, and the inhibitory interaction will no longer take place. There will remain "only" the activating interaction mediated by the MHC/Ag complex and TCR, the T lymphocyte will be activated and will proliferate.

    In the second case, the inhibitory PD1/PDL1 interaction will be broken by the administration of an anti-PD1 or anti-PDL-1 monoclonal antibody. There will then remain "only" the stimulatory action of the tumor antigen recognized by the TCR of the T lymphocyte, which will exert its cytotoxic action.

    In reality, things are more complex due to the coexistence of many simultaneous interactions between the cells involved in the T response, but numerous trials have demonstrated the relevance of this new class of anti-cancer drugs by bringing unexpected results in many cases. tumours, including melanoma, bronchial cancer, kidney cancer, ENT cancers, etc. In gynecological oncology, trials are underway, mainly in relapsed ovarian cancer sensitive to platinum salts, but very interesting prospects are emerging in certain endometrial or cervical cancers.
    However, it is not a magic weapon, because the antitumor efficacy is not always there, and because these treatments are not devoid of side effects, mimicking autoimmune diseases, which are sometimes serious. , which should be recognized and treated early. Some resistance mechanisms are beginning to appear, requiring further research to better understand the biology of cancers that we are far from fully understanding.

    Nevertheless, we are only at the beginning of the era of cancer immunotherapy, and a considerable amount of work remains to be done, to better use these new anti-cancer drugs, in monotherapy, in combination with chemotherapy, radiotherapy, see PARP inhibitors. It will be a multidisciplinary work, associating biologists, medical oncologists and radiotherapists, radiologists, without forgetting the surgeons.