Prolonged disease control with local treatments in oligo-acquired resistance to immune-checkpoint inhibitors

During the last years, immune-checkpoint inhibitors (ICIs) have been positioned as frontline treatment options for many tumor types. However, probably because of their rapid incorporation into clinical practice, many aspects regarding the intrinsic characteristics of these drugs and their effects are still unknown.

With their recently published paper, Schoenfeld et al. (1) addressed oligo-acquired resistance (oligoAR) in a cohort of 1,536 lung cancer patients treated with ICI at the Memorial Sloan Kettering Cancer Center. It is a clinical situation frequently faced by oncologists worldwide, and even though it is managed with different therapeutic strategies there is limited evidence to support them.

Up to date, a modest number of prospective studies have explored the potential benefit of local treatment of oligometastatic disease, although there is some variability in its definition on disease between trials. In patients with oligometastatic disease treated with chemotherapy, consolidation treatment with radiotherapy or surgery improves progression-free survival (PFS) and even overall survival (OS) (2-4).

Oligoprogressive disease is a slightly different clinical context, as it implies the assumption of an initial responsiveness to the systemic treatment, thus with a prognosis more favourable. Regarding local ablation of progressive lesions in patients receiving tyrosine-kinase inhibitors (TKIs) for mutation-driven tumors, it can allow the continuation of the treatment with the same drug beyond progression, although the vast majority of patients ultimately present polytopic disease progression (5-7).

Interestingly, the work by Schoenfeld et al. showed that those patients presenting oligoAR to ICI and treated with local therapy achieved a longer and greater benefit, with 58% without progression at last follow-up and 23.2% of patients maintaining disease control 2 years after the initial progression. Among the patients who received local treatment for oligoAR, 82% were treated with radiotherapy, 16% with surgical resection and 2% with radioembolization. It should be taken into account that in this study only patients treated with ICI monotherapy and not chemoimmunotherapy were included, and also required that all patients had registered a previous partial response to the treatment (1). Anyhow the results of this study are of high relevance and strongly support the local control of progressive disease when feasible, even though additional studies are required to stablish the optimal local therapy depending on the location of the lesions.

Reasons explaining this apparently greater efficacy of the local therapy in patients receiving ICI compared with patients receiving treatment with chemotherapy or TKIs might be key for a better understanding of the mechanism of action of immunotherapy. The most obvious explanation is that, as tumor antigens of the resistant clones are released after treatment with radiotherapy, these might be captured by antigen presenting cells (APCs) and presented to T lymphocytes (TLs), thus granting the control of tumor cells already present in the systemic circulation that could induce relapse in patients receiving other treatments. This would be in agreement with the abscopal effect, an immune-mediated radiological response in distant non-irradiated lesions observed after the administration of radiotherapy that is still under scientific debate (8), but on the other hand would recommend against surgical approach of oligoAR. However, further work is necessary to confirm this hypothesis, which might also imply that resistance to ICI is more dependent on changes of the tumor cells than on the immunosuppressive activity of the tumor microenvironment (TME).

This article also found differences in survival when comparing patients having one to three progressive lesions compared with those with four or more progressive lesions. Besides supporting a threshold of only three lesions to propose local treatment for patients with advanced disease receiving ICI, slightly lower than previous reports of oligoprogression with TKIs (5,7,9), it strongly suggests that oligoAR disease is a distinct entity with particular characteristics that deserves an individualized approach.

Although other different biological explanations for oligoAR have been proposed, an individual evaluation of every progressive lesion would be necessary to confirm the specific process in each case, with the additional complexity that mutual exclusivity is not mandatory.

Low bioavailability of the drug in certain tissues can favor the emergence of new lesions, which has been described for central nervous metastases in patients receiving first-generation of TKIs against epithelial growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) because of a lack of permeability of these drugs through the hemato-encephalic barrier (HEB) (7). With regard to ICI, the TME can impair antitumor efficacy both by preventing the access of the drug and by blocking immune cell infiltration (10).

Clonal heterogeneity is another main mechanism that has been associated with oligoAR, including not only DNA mutations but also epigenetic modifications that might abrogate antitumor T cell activities. Cell heterogeneity can be pre-existing because of different genetic mutations, and oligoAR would be the consequence of clonal selection of cells refractory to the immune system. Cell plasticity induced by epigenetic changes or other modifications might also favor this phenomenon (11).

Finally, the definition of oligoAR disease itself does not lack of complexity. The most sensitive imaging techniques, i.e., magnetic resonance (MR) or positron emission tomography (PET), are not routinely used for response evaluation, and some patients with widespread progressive disease might be incorrectly classified as oligoprogression. RECIST criteria 1.1 or even immune-related RECIST (irRECIST) do not take into consideration the behavior of individual lesions but the net changes in the sum of the diameters of target lesions (12). Additionally, new patterns of response to immunotherapy as pseudoprogression might act as a relevant confounding factor (13). At the end, what we are facing is the uncertainty of using radiological criteria to define a biological behaviour.

Considering all the above, if we understand oligoprogressive disease as a specific clinical outcome with distinct biological characteristics, other techniques as circulating tumor DNA (ctDNA) quantification or sequencing, as well as liquid biopsy, might be key for the diagnosis.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-50/coif). HA was supported by the Clínico Junior 2019 scholarship from the AECC (CLJUN19010ARAS). He has received honoraria for advisory roles from Astra Zeneca, for clinical trial coordination from Ferrer Farma, and accommodation/travel expenses by Takeda, MSD and Angelini Pharma. RV reports that she received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from ROCHE, AMGEM, MERCK, MSD, Lilly, Organon, and BAYER, and received support for attending meetings and/or travel from MSD, MERCK, and Lilly, and serves on a Data Safety Monitoring Board or Advisory Board of Novartis, and takes a leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid of AECC, SEOM, and ECO. MA has received honoraria for consultancy/advisory from BMS, MSD and Servier; and received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events for speaking issues from Amgen, BMS, Lilly, MSD, Roche and Servier. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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