Anales de la RANM

20 A N A L E S R A N M R E V I S T A F U N D A D A E N 1 8 7 9 TRATAMIENTO NEOADYUVANTE DEL CÁNCER DE PULMÓN Mariano Provencio Pulla An RANM · Año 2019 · número 136 (01) · páginas 17 a 24 carboplatin/pemetrexed arm. A preliminary analysis on 41 patients showed that the ORR was 64% (95% CI, 46.9–77.9) by RECIST, with the carboplatin/ pemetrexed arm having the highest response rate at 75% (95% CI, 45–93). The four complete responses occurred in the carboplatin/nab-paclitaxel arm. The toxicity profile was as expected for chemotherapy, and no pneumonitis was observed. There was one grade 5 adverse event in a patient in the carboplatin/ nab-paclitaxel arm who developed candidemia after prolonged neutropenia. Overall, the combination therapy response rates exceeded the 30% traditionally expected with platinum doublet chemotherapy; more mature data are forthcoming. Several studies in patients with NSCLC suggested an association of increased immune cell infiltration into tumours with improved survival. In recent years, improved identification of antigenic targets, the addition of immunoadjuvants, and the production of more efficient delivery systems have resulted in more efficient vaccines, able to elicit a potent immune response, leading to the development of immunotherapy for the treatment of NSCLC (29, 30). The adaptive immune response requires two signals between the antigen-presenting cells (APCs) and the effector T-cells. The first signal is mediated by the T-cell receptor and the major histocompatibility complex classes I or II antigenic peptide. The second signal is a co-stimulatory signal mediated by CD28 on the T-cell surface through binding of the B7 family members on APCs. Both signals result in the activation and clonal proliferation of T-cells. In order to avoid autoimmunity, T-cell proliferation is tightly regulated. The balance between co-stimulatory signals mediated by CD28 and co-inhibitory signals via so called immune checkpoint receptors is crucial for the maintenance of self-tolerance and to protect tissues from damage during normal immune response. After activation, T-cells express cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1, cluster of differentiation 279 [CD279]), both so called immune checkpoint receptors. CTLA-4 binds members of the B7 family with a much higher affinity than CD28 and down-regulates the T-cell response. It has been shown in pre-clinical models that one reason for the poor immunogenicity of many tumours such as lung cancer is CTLA-4 activity and that in vivo administration of antibodies to CTLA-4 can enhance antitumour immunity (31). CD4+CD25+ regulatory T-cells (Treg) that express FOXP3 represent a group of T lymphocytes that is essential for maintaining self-tolerance (32). The transcription factor FOXP3 represses IL2 transcription and up-regulates expression of CTLA- 4. FOXP3+CD25+CD4+ Treg cells constitutively express cell surface CTLA-4. CTLA4 thus maintains the immune system homeostasis by functioning as a major feedback inhibitor of T‑cell activation. PD-1 is another immune checkpoint receptor expressed on activated T‑cells. Its physiological role is to dampen the immune response in order to protect against excessive inflammation and development of autoimmunity. PD‑1 is expressed in response to inflammation and is found in many tumours. Compared with CTLA-4, PD-1 modulates a later stage of the immune response. Instead of affecting the initial stage of T-cell activation (priming) in the regional lymph node, PD-1 regulates the activation of T‑cells in peripheral tissues. Like CTLA-4, PD-1 can be found on Treg lymphocytes and also on B lymphocytes and natural killer cells. PD-1 binds to its ligands PD-L1 (B7-H1) and PD-L2 (B7-DC), which are expressed on antigen presenting cells but more importanly, also on cancer cells. While CTLA-4- and PD-1 expressing Tregs may play a critical role in maintaining self-tolerance, they also play a role in non-responsiveness to tumour antigens. It is a recognised feature of cancer cells to escape immune surveillance by expressing ligands binding to immune checkpoint receptors and the development of therapies to enhance immunogenic activity towards tumours is a rational treatment strategy. The goal of checkpoint inhibitor therapies is not to activate the immune system to attack particular targets on tumour cells, but rather to remove inhibitory pathways that block effective antitumour T‑cell responses. Tregs have been shown to be present in tumours and coexist with primed effector T‑cells. Blockade of Tregs function via anti-CTLA-4 and anti-PD-1 has the potential to remove Tregs suppression and enhance antitumour immunogenicity (33, 34). Nivolumab (BMS-936558; anti-PD-1) is a fully human monoclonal immunoglobulin G4 (IgG4) antibody (HuMAb) that targets the cell surface membrane receptor PD-1. The co-inhibitory receptor PD-1, a member of the CD28 superfamily of molecules, has important T‑cell regulatory functions. It is inducibly expressed on activated T‑cells, B‑cells, a subset of myeloid cells and a fraction of T‑memory cells, and it has been shown to mediate inhibition of T‑cell responses in peripheral tissues and tumours. Engagement of PD-1 by its natural ligands, PD-L1 and PD-L2, results in an inhibition of T‑cell proliferation, survival and cytokine secretion (35, 36). Nivolumab abrogates this interaction between PD-1 and its ligands. Nivolumab monotherapy has been approved for the treatment of advanced melanoma (FDA, EMA, and Japan) and previously treated squamous NSCLC (FDA, positive CHMP opinion). Nivolumab and ipilimumab improved PFS compared to nivolumab or ipilimumab alone in a study in melanoma (CA209067). A phase I trial tested nivolumab in 296 patients with advanced solid cancers, including 129 NSCLC patients (37, 38). Nivolumab was administered intravenously once every 2 weeks at doses of 1, 3 or 10 mg/kg. Patients continued treatment for up to IMMUNE CHECKPOINT INHIBITOR AND CHEMOTHERAPY