Correction: MRI of tumor T cell infiltration in response to checkpoint inhibitor therapy

BackgroundCheckpoint inhibitor (CPI) monotherapy is ineffective for microsatellite stable colorectal cancer (MSS-CRC). NT-I7 (efineptakin alfa) is the first-in-class long-acting IL-7 that can increase T-cell infiltration in the tumor microenvironment (TME). We hypothesize that NT-I7 may create a favorable immune-reactive TME to enhance the efficacy of CPI when combined with pembrolizumab (pembro).MethodsThis is an open-label, phase 2a study in subjects with relapsed/refractory (R/R) tumors, including CPI-naïve R/R MSS-CRC. Subjects received the recommended-phase-2-dose of NT-I7 intramuscularly at 1200 µg/kg every 6 weeks (Q6W) plus pembro 200 mg intravenously Q3W. Preliminary anti-tumor activity based on Overall Response Rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as a primary objective and by iRECIST as an exploratory objective. Biomarker analyses in peripheral blood and tumor biopsies were performed.ResultsAs of 15-July-2021, 19 subjects were enrolled in the CPI-naïve R/R MSS-CRC cohort. Six subjects are ongoing. Median age 58 years [37–81], ECOG PS 0 (26%), 1 (74%). Sixteen (84%) subjects received ≥ 2 prior therapies. All subjects had metastatic or locally advanced disease at enrollment. The median duration of follow-up was 4.64 months. Among 15 evaluable subjects, disease-control rate (DCR) based on RECIST1.1 was 47% and 1 subject achieved partial response per iRECIST (iPR) with 33% tumor reduction. Treatment-related adverse events (AEs) occurred in 14 (73.7%) subjects, 9 (47.4%) G1–2 events and 5 (26.3%) G3 events; no G4 or G5 AEs were reported. No subjects discontinued from the study due to AE. NT-I7 + pembro elicited a significant increase in the absolute lymphocyte count that peaked at week 3 (>3X from baseline, p<0.0001) and was sustained at least until week 18. CD4+/CD8+ T-cell subsets followed the same response pattern. Importantly, Stem-Cell Memory CD8+ T-cells (TSCM), the potential target for CPIs that differentiate into effectors, were remarkably increased post-study treatment (>25X from baseline, p<0.01). Plasmatic chemokines (CXCL9, CXCL10, CXCL11 and CCL9) were significantly increased after the first dose. The iPR subject had an enhanced T-cell infiltration in the TME at week 5. Subject’s follow-up continues and more updated data will be presented.ConclusionsThe chemo-free combination of NT-I7 + pembro was well tolerated and showed encouraging anti-tumor activity in subjects with CPI-naïve R/R MSS-CRC. Increased TSCM and CD8+ T-cell infiltration in TME may be the underlying mechanisms of action for the observed efficacy. These results support continued evaluation of NT-I7 + pembro in CPI-naïve subjects with R/R MSS-CRC.AcknowledgementsThe authors thank ICON for their partnership in conducting this trial.Trial RegistrationNCT04332653Ethics ApprovalThe trial was approved by MD Anderson IRB (#2020–0008_MOD001), Mary Crowley IRB (#20–13) and Advarra IRB (#Pro00042639)All participant gave informed consent prior to study enrollment.

Download Full-text

MRI of tumor T cell infiltration in response to checkpoint inhibitor therapy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000328 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000328 ◽

Cited By ~ 1

Author(s):

Xiaoyu Jiang ◽

Stephanie Dudzinski ◽

Kathryn E Beckermann ◽

Kirsten Young ◽

Eliot McKinley ◽

...

Keyword(s):

T Cell ◽

Tumor Growth ◽

Cell Size ◽

Immune Checkpoint ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Cell Infiltration ◽

Response Criteria ◽

Non Invasive ◽

T Cell Infiltration

BackgroundImmune checkpoint inhibitors, the most widespread class of immunotherapies, have demonstrated unique response patterns that are not always adequately captured by traditional response criteria such as the Response Evaluation Criteria in Solid Tumors or even immune-specific response criteria. These response metrics rely on monitoring tumor growth, but an increase in tumor size and/or appearance after starting immunotherapy does not always represent tumor progression, but also can be a result of T cell infiltration and thus positive treatment response. Therefore, non-invasive and longitudinal monitoring of T cell infiltration are needed to assess the effects of immunotherapies such as checkpoint inhibitors. Here, we proposed an innovative concept that a sufficiently large influx of tumor infiltrating T cells, which have a smaller diameter than cancer cells, will change the diameter distribution and decrease the average size of cells within a volume to a degree that can be quantified by non-invasive MRI.MethodsWe validated our hypothesis by studying tumor response to combination immune-checkpoint blockade (ICB) of anti-PD-1 and anti-CTLA4 in a mouse model of colon adenocarcinoma (MC38). The response was monitored longitudinally using Imaging Microstructural Parameters Using Limited Spectrally Edited Diffusion (IMPULSED), a diffusion MRI-based method which has been previously shown to non-invasively map changes in intracellular structure and cell sizes with the spatial resolution of MRI, in cell cultures and in animal models. Tumors were collected for immunohistochemical and flow cytometry analyzes immediately after the last imaging session.ResultsImmunohistochemical analysis revealed that increased T cell infiltration of the tumors results in a decrease in mean cell size (eg, a 10% increase of CD3+ T cell fraction results a ~1 µm decrease in the mean cell size). IMPULSED showed that the ICB responders, mice with tumor volumes were less than 250 mm3 or had tumors with stable or decreased volumes, had significantly smaller mean cell sizes than both Control IgG-treated tumors and ICB non-responder tumors.ConclusionsIMPULSED-derived cell size could potentially serve as an imaging marker for differentiating responsive and non-responsive tumors after checkpoint inhibitor therapies, a current clinical challenge that is not solved by simply monitoring tumor growth.

Download Full-text

Abstract 3091: Liquid biopsy reflecting a T-cell permissive tumor microenvironment identifies metastatic melanoma patients responding to immune checkpoint inhibitor therapy

10.1158/1538-7445.am2020-3091 ◽

2020 ◽

Author(s):

Christina Jensen ◽

Dovile Sinkeviciute ◽

Daniel H. Madsen ◽

Patrik Önnerfjord ◽

Morten Hansen ◽

...

Keyword(s):

T Cell ◽

Tumor Microenvironment ◽

Metastatic Melanoma ◽

Immune Checkpoint ◽

Liquid Biopsy ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Inhibitor Therapy ◽

Checkpoint Inhibitor Therapy ◽

Melanoma Patients

Download Full-text

Immune Checkpoint Inhibitor Therapy Aggravates T Cell–Driven Plaque Inflammation in Atherosclerosis

JACC: CardioOncology ◽

10.1016/j.jaccao.2020.08.007 ◽

2020 ◽

Vol 2 (4) ◽

pp. 599-610 ◽

Cited By ~ 1

Author(s):

Kikkie Poels ◽

Mandy M.T. van Leent ◽

Celine Boutros ◽

Hubert Tissot ◽

Séverine Roy ◽

...

Keyword(s):

T Cell ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Inhibitor Therapy ◽

Checkpoint Inhibitor Therapy ◽

Plaque Inflammation

Download Full-text

Enhancing Checkpoint Inhibitor Therapy in Solid Tissue Cancers: The Role of Diet, the Microbiome & Microbiome-Derived Metabolites

Frontiers in Immunology ◽

10.3389/fimmu.2021.624434 ◽

2021 ◽

Vol 12 ◽

Author(s):

Agnieszka Beata Malczewski ◽

Natkunam Ketheesan ◽

Jermaine I. G. Coward ◽

Severine Navarro

Keyword(s):

T Cell ◽

Checkpoint Inhibitor ◽

Short Chain Fatty Acids ◽

Potential Effect ◽

Preliminary Evidence ◽

Inhibitor Therapy ◽

Fecal Transplantation ◽

Solid Tissue ◽

Checkpoint Inhibitor Therapy

Host immunity plays a central role in the regulation of anti-tumour responses during checkpoint inhibitor therapy (CIT). The mechanisms involved in long lasting remission remain unclear. Animal studies have revealed that the microbiome influences the host immune response. This is supported by human studies linking a higher microbial richness and diversity with enhanced responses to CIT. This review focuses on the role of diet, the microbiome and the microbiome-derived metabolome in enhancing responses to current CIT in solid tissue cancers. The Western diet has been associated with dysbiosis, inflammation and numerous metabolic disorders. There is preliminary evidence that lifestyle factors including a high fibre diet are associated with improved responses to CIT via a potential effect on the microbiota. The mechanisms through which the microbiota may regulate long-term immunotherapy responses have yet to be determined, although bacterial-metabolites including short chain fatty acids (SCFAs) are recognized to have an impact on T cell differentiation, and may affect T effector/regulatory T cell balance. SCFAs were also shown to enhance the memory potential of activated CD8 T cells. Many therapeutic approaches including dietary manipulation and fecal transplantation are currently being explored in order to enhance immunotherapy responses. The microbiome-derived metabolome may be one means through which bacterial metabolic products can be monitored from the start of treatment and could be used to identify patients at risk of poor immunotherapy responses. The current review will discuss recent advances and bring together literature from related fields in nutrition, oncology and immunology to discuss possible means of modulating immunity to improve responses to current CIT.

Download Full-text