Clinical and molecular parameters associated to pneumonitis development in non-small-cell lung cancer patients receiving chemoimmunotherapy from NADIM trial
Sierra-Rodero, Belén (Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana)
Cruz-Bermúdez, Alberto (Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana)
Nadal, Ernest (Institut d'Investigació Biomèdica de Bellvitge)
Garitaonaindiá, Yago (Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana)
Insa, Amelia (INCLIVA. Valencia)
Mosquera, Joaquín (Complejo Hospitalario Universitario de A Coruña)
Casal-Rubio, Joaquín (Hospital Universitario de Vigo)
Dómine, Manuel (Hospital Universitario Fundación Jiménez Díaz)
Majem, Margarita (Institut d'Investigació Biomèdica Sant Pau)
Rodríguez-Abreu, Delvys (Hospital Universitario Insular de Gran Canaria)
Martinez-Marti, Alex (Vall d'Hebron Institut d'Oncologia)
de Castro, Javier (Hospital Universitario La Paz (Madrid))
Cobo, Manuel (Hospital Regional Universitario de Málaga)
López Vivanco, Guillermo (Hospital Universitario de Cruces (Barakaldo, País Basc))
Del Barco Morillo, Edel (Hospital Universitario de Salamanca)
Bernabé, Reyes (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Viñolas, Nuria (Hospital Clínic i Provincial de Barcelona)
Barneto Aranda, Isidoro (Hospital Universitario Reina Sofía (Còrdova, Espanya))
Viteri, Santiago (Instituto Oncológico Dr. Rosell. Hospital Universitario Quiron Dexeus)
Massuti, Bartomeu (Hospital General Universitario de Alicante (Alacant, País Valencià))
Laza-Briviesca, Raquel (Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana)
Casarrubios, Marta (Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana)
Garciá-Grande, Aránzazu (Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana)
Romero, Atocha (Hospital Universitario Puerta de Hierro Majadahonda (Madrid))
Franco, Fernando (Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana)
Provencio, Mariano (Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana)

Fecha:	2021
Resumen:	Background Pneumonitis (Pn) is one of the main immune-related adverse effects, having a special importance in lung cancer, since they share affected tissue. Despite its clinical relevance, Pn development remains an unpredictable treatment adverse effect, whose mechanisms are mainly unknown, being even more obscure when it is associated to chemoimmunotherapy. Methods In order to identify parameters associated to treatment related Pn, we analyzed clinical variables and molecular parameters from 46 patients with potentially resectable stage IIIA non-small-cell lung cancer treated with neoadjuvant chemoimmunotherapy included in the NADIM clinical trial (NCT03081689). Pn was defined as clinical or radiographic evidence of lung inflammation without alternative diagnoses, from treatment initiation to 180 days. Results Among 46 patients, 12 developed Pn (26. 1%). Sex, age, smoking status, packs-year, histological subtype, clinical or pathological response, progression-free survival, overall survival and number of nivolumab cycles, were not associated to Pn development. Regarding molecular parameters at diagnosis, Pn development was not associated to programmed death ligand 1, TPS, T cell receptor repertoire parameters, or tumor mutational burden. However, patients who developed Pn had statistically significant lower blood median levels of platelet to monocyte ratio (p=0. 012) and teratocarcinoma-derived growth factor 1 (p=0. 013; area under the curve (AUC) 0. 801), but higher median percentages of natural killers (NKs) (p=0. 019; AUC 0. 786), monocytes (p=0. 017; AUC 0. 791), MSP (p=0. 006; AUC 0. 838), PARN (p=0. 017; AUC 0. 790), and E-Cadherin (p=0. 022; AUC 0. 788). In addition, the immune scenario of Pn after neoadjuvant treatment involves: high levels of neutrophils and NK cells, but low levels of B and T cells in peripheral blood; increased clonality of intratumoral T cells; and elevated plasma levels of several growth factors (EGF, HGF, VEGF, ANG-1, PDGF, NGF, and NT4) and inflammatory cytokines (MIF, CCL16, neutrophil gelatinase-associated lipocalin, BMP-4, and u-PAR). Conclusions Although statistically underpowered, our results shed light on the possible mechanisms behind Pn development, involving innate and adaptative immunity, and open the possibility to predict patients at high risk. If confirmed, this may allow the personalization of both, the surveillance strategy and the therapeutic approaches to manage Pn in patients receiving chemoimmunotherapy.
Ayudas:	Instituto de Salud Carlos III PI19/01652 Ministerio de Ciencia e Innovación RTC2017-6502-1 Ministerio de Ciencia e Innovación RTC2019-007359-1 European Commission. Horizon 2020 875160 Instituto de Salud Carlos III CD19/00170
Nota:	Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER); Bristol-Myers Squibb (BMS); Grupo Español de Cáncer de Pulmón (GECP); European Social Fund (ESF) i Comunidad de Madrid (PEJD-2019-PRE/BMD-17006, PEJ16/MED/AI-1972, PEJD-2018-PRE/SAL-8641).
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	Journal for immunotherapy of cancer, Vol. 9 Núm. 8 (august 2021) , p. e002804, ISSN 2051-1426

DOI: 10.1136/jitc-2021-002804
PMID: 34446577

13 p, 2.9 MB

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