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Next Generation Immuno-Oncology Strategies: Unleashing NK Cells Activity.

ABSTRACT: In recent years, immunotherapy has become a powerful therapeutic option against multiple malignancies. The unique capacity of natural killer (NK) cells to attack cancer cells without antigen specificity makes them an optimal immunotherapeutic tool for targeting tumors. Several approaches are currently being pursued to maximize the anti-tumor properties of NK cells in the clinic, including the development of NK cell expansion protocols for adoptive transfer, the establishment of a favorable microenvironment for NK cell activity, the redirection of NK cell activity against tumor cells, and the blockage of inhibitory mechanisms that constrain NK cell function. We here summarize the recent strategies in NK cell-based immunotherapies and discuss the requirement to further optimize these approaches for enhancement of the clinical outcome of NK cell-based immunotherapy targeting tumors.

SUBMITTER: Mendoza-Valderrey A

PROVIDER: S-EPMC9562848 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Next Generation Immuno-Oncology Strategies: Unleashing NK Cells Activity.

Mendoza-Valderrey Alberto A Alvarez Maite M De Maria Andrea A Margolin Kim K Melero Ignacio I Ascierto Maria Libera ML

Cells 20221006 19

In recent years, immunotherapy has become a powerful therapeutic option against multiple malignancies. The unique capacity of natural killer (NK) cells to attack cancer cells without antigen specificity makes them an optimal immunotherapeutic tool for targeting tumors. Several approaches are currently being pursued to maximize the anti-tumor properties of NK cells in the clinic, including the development of NK cell expansion protocols for adoptive transfer, the establishment of a favorable micro ...[more]

PMID: 36231109

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Project description:BackgroundCancers escape immune surveillance via distinct mechanisms that involve central (negative selection within the thymus) or peripheral (lack of costimulation, receipt of death/anergic signals by tumor, immunoregulatory cell populations) immune tolerance. During the 1990s, moderate clinical benefit was seen using several cytokine therapies for a limited number of cancers. Over the past 20 years, extensive research has been performed to understand the role of various components of peripheral immune tolerance, with the co-inhibitory immune checkpoint molecules cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand (PD-L1) being the most well-characterized at preclinical and clinical levels.Patients and methodsWe used PubMed and Google Scholar searches to identify key articles published reporting preclinical and clinical studies investigating CTLA-4 and PD-1/PD-L1, frequently cited review articles, and clinical studies of CTLA-4 and PD-1/PD-L1 pathway inhibitors, including combination therapy strategies. We also searched recent oncology congress presentations and clinicaltrials.gov to cover the most up-to-date clinical trial data and ongoing clinical trials of immune checkpoint inhibitor (ICI) combinations.ResultsInhibiting CTLA-4 and PD-1 using monoclonal antibody therapies administered as single agents has been associated with clinical benefit in distinct patient subgroups across several malignancies. Concurrent blockade of CTLA-4 and components of the PD-1/PD-L1 system using various schedules has shown synergy and even higher incidence of durable antitumor responses at the expense of increased rates of immune-mediated adverse events, which can be life-threatening, but are rarely fatal and are reversible in most cases using established treatment guidelines.ConclusionsDual immune checkpoint blockade has demonstrated promising clinical benefit in numerous solid tumor types. This example of concurrent modulation of multiple components of the immune system is currently being investigated in other cancers using various immunomodulatory strategies.

Project description:BackgroundImmuno-oncology (IO) therapies targeting the PD-1/PD-L1 axis, such as immune checkpoint inhibitor (ICI) antibodies, have emerged as promising treatments for early-stage breast cancer (ESBC). Despite immunotherapy's clinical significance, the number of benefiting patients remains small, and the therapy can prompt severe immune-related events. Current pathologic and transcriptomic predictions of IO response are limited in terms of accuracy and rely on single-site biopsies, which cannot fully account for tumor heterogeneity. In addition, transcriptomic analyses are costly and time-consuming. We therefore constructed a computational biomarker coupling biophysical simulations and artificial intelligence-based tissue segmentation of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRIs), enabling IO response prediction across the entire tumor.MethodsBy analyzing both single-cell and whole-tissue RNA-seq data from non-IO-treated ESBC patients, we associated gene expression levels of the PD-1/PD-L1 axis with local tumor biology. PD-L1 expression was then linked to biophysical features derived from DCE-MRIs to generate spatially- and temporally-resolved atlases (virtual tumors) of tumor biology, as well as the TumorIO biomarker of IO response. We quantified TumorIO within patient virtual tumors (n = 63) using integrative modeling to train and develop a corresponding TumorIO Score.ResultsWe validated the TumorIO biomarker and TumorIO Score in a small, independent cohort of IO-treated patients (n = 17) and correctly predicted pathologic complete response (pCR) in 15/17 individuals (88.2% accuracy), comprising 10/12 in triple negative breast cancer (TNBC) and 5/5 in HR+/HER2- tumors. We applied the TumorIO Score in a virtual clinical trial (n = 292) simulating ICI administration in an IO-naïve cohort that underwent standard chemotherapy. Using this approach, we predicted pCR rates of 67.1% for TNBC and 17.9% for HR+/HER2- tumors with addition of IO therapy; comparing favorably to empiric pCR rates derived from published trials utilizing ICI in both cancer subtypes.ConclusionThe TumorIO biomarker and TumorIO Score represent a next generation approach using integrative biophysical analysis to assess cancer responsiveness to immunotherapy. This computational biomarker performs as well as PD-L1 transcript levels in identifying a patient's likelihood of pCR following anti-PD-1 IO therapy. The TumorIO biomarker allows for rapid IO profiling of tumors and may confer high clinical decision impact to further enable personalized oncologic care.

Dataset Information

Next Generation Immuno-Oncology Strategies: Unleashing NK Cells Activity.

Publications

Next Generation Immuno-Oncology Strategies: Unleashing NK Cells Activity.

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