Oligoprogression (OPD) of non-small-cell lung cancer (NSCLC) occurs in approximately half of patients under targeted compounds (TKI) and facilitates use of regional therapies that can prolong survival. In order to characterize OPD in immunotherapy (IO)-treated NSCLC, we analyzed the failure pattern under PD-1/PD-L1 inhibitors (n = 297) or chemoimmunotherapy (n = 75). Under IO monotherapy, OPD was more frequent (20% vs. 10%, p < 0.05), occurred later (median 11 vs. 5 months, p < 0.01), affected fewer sites (mean 1.1 vs. 1.5, p < 0.05), and involved fewer lesions (1.4 vs. 2.3, p < 0.05) in the first compared to later lines. Lymph nodes (42%, mainly mediastinal) and the brain (39%) were mostly affected, followed by the lung (24%) and other organs. Compared to multifocal progression, OPD occurred later (11 vs. 4 months, p < 0.001) and was associated with longer survival (26 vs. 13 months, p < 0.001) and higher tumor PD-L1 expression (p < 0.001). Chemoimmunotherapy showed a similar incidence of OPD as IO monotherapy (13% vs. 11% at 2 years). Local treatments were applied regularly for brain but only in 50% for extracranial lesions. Thus, NSCLC oligoprogression is less common under IO than under TKI, but also favorable. Since its frequency drops later in the disease, regular restaging and multidisciplinary evaluation are essential in order to exploit the full therapeutic potential.

Immune checkpoint inhibitors have redefined the treatment of cancer, but their efficacy depends critically on the presence of sufficient tumor-specific lymphocytes, and cellular immunotherapies develop rapidly to fill this gap. The paucity of suitable extracellular and tumor-associated antigens in solid cancers necessitates the use of neoantigen-directed T-cell-receptor (TCR)-engineered cells, while prevention of tumor evasion requires combined targeting of multiple neoepitopes. These can be currently identified within 2 weeks by combining cutting-edge next-generation sequencing with bioinformatic pipelines and used to select tumor-reactive TCRs in a high-throughput manner for expeditious scalable non-viral gene editing of autologous or allogeneic lymphocytes. “Young” cells with a naive, memory stem or central memory phenotype can be additionally armored with “next-generation” features against exhaustion and the immunosuppressive tumor microenvironment, where they wander after reinfusion to attack heavily pretreated and hitherto hopeless neoplasms. Facilitated by major technological breakthroughs in critical manufacturing steps, based on a solid preclinical rationale, and backed by rapidly accumulating evidence, TCR therapies break one bottleneck after the other and hold the promise to become the next immuno-oncological revolution.