Lung cancer is the second leading cause of death in men and the third leading cause in women. It can exist in benign and malignant forms; the latter are divided into two main phenotypes (small cell, SCLC, and non-small cell, NSCLC) and further subclasses depending on histology and genetic aberrations. In the era of precision medicine, oncology can no longer be limited to the use of cytotoxic drugs alone. The target therapies, and especially immunotherapy, are cornestones of the exploration of new frontiers which aim to offer a wider range of therapeutic options to patients. Immunotherapy has led to a real revolution in the treatment of different tumoral forms, allowing to highlight both objective responses, i.e. the reduction of the tumor mass, and the increase in survival compared to traditional therapies such as chemotherapy, radiotherapy and target therapies. The rationale for applying immunotherapy in the fight against cancer is based on the ability to block the escape mechanisms implemented by cancer cells and stimulate the immune system from the outside, in order to make it competent again. Immunotherapy is divided into two main classes: passive immunotherapy, used against cancer in patients with weak or compromised immune systems, and active immunotherapy, which has the task of stimulating the immune effectors in vivo and it's suitable for immunocompetent individuals. Passive immunotherapy in NSCLC mainly involves the use of monoclonal antibodies (mAbs), which can be naked or conjugated and bispecific, and adoptive cell transfer (ACT), carried out with different techniques: in vitro expansion of tumor infiltrating lymphocytes (TILs), CIK therapy, CAPRI therapy, T lymphocyte receptor engineering (TCR) and CAR-T therapy. In contrast, active immunotherapy includes therapeutic anti-cancer vaccines, immune checkpoint inhibitors (ICI), namely CTLA-4, the PD-1 / PD-L1 axis and some still under study (OX-40, 4 -1BB, CD-40, LAG-3, TIM-3, TIGIT, KIR and VISTA), and oncolytic viruses. Most of these drugs have received the designation of orphan and / or innovative drugs from the two of the top exponents of world health, FDA and EMA. Surely the keystone in the development of immunotherapy was the discovery of immune checkpoints, which play a key role in tumor masking. To date, two PD-1 inhibitors (nivolumab and pembrolizumab) and two PD-L1 inhibitors (atezolizumab and durvalumab) have been approved by EMA and FDA. They are drugs that have revolutionized the treatment of non-small cell lung cancer; in particular, pembrolizumab, with its very high therapeutic potential, in recent years has obtained authorization as the first line of treatment patients with wild-type NSCLC with PD-L1 expression ≥ 50%. Moreover, immunotherapy is revolutionizing cancer treatment thanks to its lower side effects due to the increasingly selective action mechanisms against the therapeutic target of interest, safeguarding self cells. Despite the promising results of cancer immunotherapy, nowadays only 20% of patients are able to obtain clinically significant benefits, especially due to the establishment of resistance mechanisms. For this reason, research is also moving towards the identification of increasingly reliable predictive markers response for treatment to select patients eligible for treatment with immune agents, while considering the cost of these molecules and their impact on health systems.
Il tumore al polmone è la principale seconda causa di morte nel sesso maschile e la terza in quello femminile. Può esistere in forme benigne e maligne; quest’ultime sono suddivise in due fenotipi principali (a piccole cellule, SCLC, e non a piccole cellule, NSCLC) e ulteriori sottoclassi in base all’istologia e aberrazioni genetiche. Nell’era della “precision medicine” l’oncologia non può più limitarsi all’impiego dei soli farmaci citotossici. Le target therapies e soprattutto l’immunoterapia hanno portato all’esplorazione di nuove frontiere per offrire una sempre più vasta gamma di opzioni terapeutiche ai pazienti. L’immunoterapia ha portato ad una vera e propria rivoluzione nel trattamento di diverse forme tumorali, consentendo di evidenziare sia risposte obiettive, ossia riduzione della massa tumorale, che l’incremento della sopravvivenza rispetto alle terapie tradizionali come chemioterapia, radioterapia e target therapies. Il razionale dell’applicazione dell’immunoterapia nella lotta al cancro si fonda sulla capacità di bloccare i meccanismi di evasione messi in atto dalle cellule tumorali e stimolare dall’esterno il sistema immunitario al fine di renderlo nuovamente competente. L’immunoterapia viene divisa in due classi principali: l’immunoterapia passiva, impiegata contro il cancro in pazienti con sistema immunitario debole o compromesso, e l’immunoterapia attiva, la quale ha il compito di stimolare gli effettori immunitari in vivo ed è idonea per gli individui immunocompetenti. L’immunoterapia passiva nel NSCLC vede principalmente l’uso di anticorpi monoclonali (mAbs), che possono essere nudi o coniugati e bispecifici, e il trasferimento adottivo di cellule (ACT), realizzato con diverse tecniche: espansione in vitro di linfociti infiltranti il tumore (TILs), terapia CIK, terapia CAPRI, ingegnerizzazione del recettore dei linfociti T (TCR) e terapia CAR-T. Al contrario, l’immunoterapia attiva comprende i vaccini terapeutici anticancro, gli inibitori del checkpoint immunitario (ICI), ovvero CTLA-4, l’asse PD-1/PD-L1 e alcuni ancora in fase di studio (OX-40, 4-1BB, CD-40, LAG-3, TIM-3, TIGIT, KIR e VISTA), e i virus oncolitici. Molti di questi farmaci hanno ottenuto la denominazione di farmaci orfani e/o innovativi dai due massimi esponenti della sanità mondiale, FDA e EMA. Sicuramente la chiave di volta nello sviluppo dell’immunoterapia è stata la scoperta dei checkpoint immunitari, che svolgono un ruolo chiave nel mascheramento tumorale. Ad oggi sono stati approvati da EMA e FDA due inibitori di PD-1 (nivolumab e pembrolizumab) e due inibitori di PD-L1 (atezolizumab e durvalumab). Sono farmaci che hanno rivoluzionato il trattamento del carcinoma polmonare non a piccole cellule; in particolare, pembrolizumab con il suo altissimo potenziale terapeutico negli ultimi anni ha ottenuto l’autorizzazione come prima linea di trattamento per quel gruppo di pazienti affetti da NSCLC wild-type con espressione di PD-L1 ≥ 50%. L’immunoterapia sta rivoluzionando la cura oncologica anche per i suoi minori effetti collaterali in virtù di meccanismi d’azione sempre più selettivi contro il bersaglio terapeutico d’interesse, salvaguardando le cellule self. Nonostante i promettenti risultati dell’immunoterapia oncologica, ad oggi solo il 20% dei pazienti riescono a ottenere benefici clinicamente significativi, specialmente a causa dell’instaurarsi di meccanismi di resistenza. Per questa ragione la ricerca si sta muovendo anche verso l’identificazione di markers predittivi di risposta a trattamento sempre più affidabili per selezionare pazienti candidabili a trattamento con agenti immunitari, considerando anche il costo di queste molecole e il loro impatto sui sistemi sanitari.
Le nuove frontiere immunoterapiche per il trattamento del carcinoma polmonare non a piccole cellule (NSCLC)
BIANCHI, FRANCESCA
2019/2020
Abstract
Lung cancer is the second leading cause of death in men and the third leading cause in women. It can exist in benign and malignant forms; the latter are divided into two main phenotypes (small cell, SCLC, and non-small cell, NSCLC) and further subclasses depending on histology and genetic aberrations. In the era of precision medicine, oncology can no longer be limited to the use of cytotoxic drugs alone. The target therapies, and especially immunotherapy, are cornestones of the exploration of new frontiers which aim to offer a wider range of therapeutic options to patients. Immunotherapy has led to a real revolution in the treatment of different tumoral forms, allowing to highlight both objective responses, i.e. the reduction of the tumor mass, and the increase in survival compared to traditional therapies such as chemotherapy, radiotherapy and target therapies. The rationale for applying immunotherapy in the fight against cancer is based on the ability to block the escape mechanisms implemented by cancer cells and stimulate the immune system from the outside, in order to make it competent again. Immunotherapy is divided into two main classes: passive immunotherapy, used against cancer in patients with weak or compromised immune systems, and active immunotherapy, which has the task of stimulating the immune effectors in vivo and it's suitable for immunocompetent individuals. Passive immunotherapy in NSCLC mainly involves the use of monoclonal antibodies (mAbs), which can be naked or conjugated and bispecific, and adoptive cell transfer (ACT), carried out with different techniques: in vitro expansion of tumor infiltrating lymphocytes (TILs), CIK therapy, CAPRI therapy, T lymphocyte receptor engineering (TCR) and CAR-T therapy. In contrast, active immunotherapy includes therapeutic anti-cancer vaccines, immune checkpoint inhibitors (ICI), namely CTLA-4, the PD-1 / PD-L1 axis and some still under study (OX-40, 4 -1BB, CD-40, LAG-3, TIM-3, TIGIT, KIR and VISTA), and oncolytic viruses. Most of these drugs have received the designation of orphan and / or innovative drugs from the two of the top exponents of world health, FDA and EMA. Surely the keystone in the development of immunotherapy was the discovery of immune checkpoints, which play a key role in tumor masking. To date, two PD-1 inhibitors (nivolumab and pembrolizumab) and two PD-L1 inhibitors (atezolizumab and durvalumab) have been approved by EMA and FDA. They are drugs that have revolutionized the treatment of non-small cell lung cancer; in particular, pembrolizumab, with its very high therapeutic potential, in recent years has obtained authorization as the first line of treatment patients with wild-type NSCLC with PD-L1 expression ≥ 50%. Moreover, immunotherapy is revolutionizing cancer treatment thanks to its lower side effects due to the increasingly selective action mechanisms against the therapeutic target of interest, safeguarding self cells. Despite the promising results of cancer immunotherapy, nowadays only 20% of patients are able to obtain clinically significant benefits, especially due to the establishment of resistance mechanisms. For this reason, research is also moving towards the identification of increasingly reliable predictive markers response for treatment to select patients eligible for treatment with immune agents, while considering the cost of these molecules and their impact on health systems.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/11806