Transdermal cold atmospheric plasma-mediated immune checkpoint blockade therapy

Despite the promise of immune checkpoint blockade (ICB) therapy against cancer, challenges associated with low objective response rates and severe systemic side effects still remain and limit its clinical applications. Here, we described a cold atmospheric plasma (CAP)-mediated ICB therapy integrated with microneedles (MN) for the transdermal delivery of ICB. We found that a hollow-structured MN (hMN) patch facilitates the transportation of CAP through the skin, causing tumor cell death. The release of tumor-associated antigens then promotes the maturation of dendritic cells in the tumor-draining lymph nodes, subsequently initiating T cell-mediated immune response. Anti-programmed death-ligand 1 antibody (aPDL1), an immune checkpoint inhibitor, released from the MN patch further augments the antitumor immunity. Our findings indicate that the proposed transdermal combined CAP and ICB therapy can inhibit the tumor growth of both primary tumors and distant tumors, prolonging the survival of tumor-bearing mice.

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Faculty Opinions recommendation of Transdermal cold atmospheric plasma-mediated immune checkpoint blockade therapy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.737334274.793572096 ◽

2020 ◽

Author(s):

Xiaoming He

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Atmospheric Plasma ◽

Cold Atmospheric Plasma

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Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Patterns of Response and Survival According to the Presence of Hepatic and Extrahepatic Metastasis

Cancers ◽

10.3390/cancers13133359 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3359

Author(s):

Elias Koch ◽

Anne Petzold ◽

Anja Wessely ◽

Edgar Dippel ◽

Anja Gesierich ◽

...

Keyword(s):

Skin Cancer ◽

Uveal Melanoma ◽

Hepatic Metastasis ◽

Immune Checkpoint ◽

Objective Response ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Response To Treatment ◽

Extrahepatic Metastasis ◽

The Impact

Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan–Meier method. Log-rank tests, χ2 tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4–23.7) and the median PFS, 2.8 months (95% CI 2.5–3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.

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Real-world experience and molecular features of response to immune checkpoint blockade in patients with recurrent small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.8556 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 8556-8556 ◽

Cited By ~ 1

Author(s):

Wei-Chu Victoria Lai ◽

Hira Rizvi ◽

Jacklynn V. Egger ◽

Andrew J. Plodkowski ◽

Michelle S. Ginsberg ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Real World ◽

Immune Checkpoint ◽

Objective Response ◽

Immune Checkpoint Blockade ◽

Small Cell ◽

Checkpoint Blockade ◽

Small Cell Lung

8556 Background: Immune checkpoint blockade (ICB) is now a routine component of treatment in recurrent small cell lung cancer (SCLC). We evaluated the response to ICB in patients (pts) with recurrent SCLC and genomic features of response using next-generation sequencing (NGS). Methods: Pts with recurrent SCLC treated with ICB were identified. The majority of pts were treated outside of a clinical trial to focus emphasis on the real-world experience. Tumor mutation burden (TMB) and the landscape of somatic variants were determined by targeted NGS using MSK-IMPACT. Objective response rate (ORR) to ICB was determined using RECIST v1.1. PFS and OS were measured from the start of ICB and analyzed using Kaplan-Meier. Results: Between December 2013 and October 2018, 108 pts with SCLC were treated with ICB (57 subjected to NGS). Pts received PD-1 monotherapy alone (n = 28) or in combination with CTLA-4 blockade (n = 80). Median line of therapy was 2 (range 1-6). ORR was 14% (15/108, 95% CI 8-22%). From the start of ICB, median PFS was 1.4 months in non-responders and 10.8 months in responders (HR 0.2; 95% CI 0.13-0.32). Median OS was 6.3 months in non-responders and undefined in responders (range 8-44 months) (HR 0.26, 95% CI 0.16-0.44). Four responders remain on ICB treatment. TMB in the ICB-treated cohort was similar to that of an unselected cohort (n = 233) of SCLC (median 8.8 Mt/MB vs 8.2 Mt/MB, p = 0.71). Clinical benefit was enriched among those with a higher TMB (upper vs middle/lower tertile PFS HR 0.48, 95% CI 0.28-0.84, p = 0.01 and ORR 26% [5/19] vs ORR 8% [3/38]). Rates of whole genome duplication and commonly altered genes in SCLC ( TP53, RB1, KMT2C/D, NOTCH1/2/4, PTPRD, APC) were similarly distributed across responders and non-responders. Completion of whole-exome sequencing and PD-L1 testing is in progress. Conclusions: In pts with recurrent SCLC receiving routine clinical care, the ORR to ICB is comparable to reports from clinical trials. A high TMB was associated with a longer median PFS and better response. Further investigation into the genomic landscape of recurrent SCLC is needed to identify biomarkers predictive of response to ICB.

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Detecting Early Response to Immune Checkpoint Blockade by Multimodal Molecular Imaging

10.1101/2020.04.30.070508 ◽

2020 ◽

Author(s):

Yu Saida ◽

Jeffery R. Brender ◽

Kazutoshi Yamamoto ◽

James B. Mitchell ◽

Murali C. Krishna ◽

...

Keyword(s):

Treatment Group ◽

Immune Checkpoint ◽

Early Response ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Qualitative Assessment ◽

Imaging Biomarkers ◽

Tumor Cell Death ◽

Dynamic Contrast Enhanced ◽

Contrast Enhanced

AbstractImmune checkpoint inhibitors have become a standard therapy for several cancers; however, the response is inconsistent and a method for non-invasive assessment has not been established to date. To investigate the capability of multi-modal imaging to evaluate treatment response to immune checkpoint blockade therapy, we employed hyperpolarized 13C MRI on tumor bearing mice using [1-13C] pyruvate and [1,4-13C2] fumarate to detect early changes in tumor glycolysis and necrosis, respectively. Following αPD-L1 Ab + αCTLA-4 Ab dual immune checkpoint blockade (ICB) therapy, dynamic contrast enhanced (DCE) MRI was used to determine the treatment effect on intratumor perfusion/permeability. Mice bearing MC38 colon adenocarcinoma and B16.F10 melanoma were used as sensitive and less sensitive models, respectively to immune checkpoint dual blockade of PD-L1 and CTLA-4. Glycolytic flux significantly decreased upon treatment in the less ICB sensitive B16.F10 model but remained essentially unchanged in MC38 tumors. Imaging [1,4-13C] fumarate conversion to [1,4-13C] malate showed a significant increase in necrosis in the treatment group for the ICB sensitive MC38 tumor (p = 0.0003), with essentially no change in ICB sensitive B16.F10 tumors. Histological assessment showed increased necrotic tissue with enhanced lymphocyte infiltration in the MC38 treatment group, suggesting immunogenic tumor cell death. Dynamic contrast enhanced MRI showed significantly increased perfusion/permeability of Gd-DTPA in MC38 treated tumor, while a similar trend but statistically non-significant change was observed in B16.F10 treated tumor. These results provide imaging biomarkers to detect early response to cancer immunotherapy, allowing qualitative assessment of tumors treated with immune checkpoint blockade therapy.

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PD-1 blockade in tumors with mismatch repair deficiency.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.18_suppl.lba100 ◽

2015 ◽

Vol 33 (18_suppl) ◽

pp. LBA100-LBA100 ◽

Cited By ~ 17

Author(s):

Dung T. Le ◽

Jennifer N. Uram ◽

Hao Wang ◽

Bjarne Bartlett ◽

Holly Kemberling ◽

...

Keyword(s):

Mismatch Repair ◽

Immune Checkpoint ◽

Somatic Mutations ◽

Objective Response ◽

Progression Free Survival ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Clinical Activity ◽

Primary Endpoints ◽

Repair Deficiency

LBA100 Background: Somatic mutations have the potential to be recognized as “non-self” immunogenic antigens. Tumors with genetic defects in mismatch repair (MMR) harbor many more mutations than tumors of the same type without such repair defects. We hypothesized that tumors with mismatch repair defects would therefore be particularly susceptible to immune checkpoint blockade. Methods: We conducted a phase II study to evaluate the clinical activity of anti-PD-1, pembrolizumab, in 41 patients with previously-treated, progressive metastatic disease with and without MMR-deficiency. Pembrolizumab was administered at 10 mg/kg intravenously every 14 days to three cohorts of patients: those with MMR-deficient colorectal cancers (CRCs) (N = 11); those with MMR-proficient CRCs (N = 21), and those with MMR-deficient cancers of types other than colorectal (N = 9). The co-primary endpoints were immune-related objective response rate (irORR) and immune-related progression-free survival (irPFS) at 20 weeks. Results: The study met its primary endpoints for both MMR-deficient cohorts. The irORR and irPFS at 20 weeks for MMR-deficient CRC were 40% and 78%, respectively, and for MMR-deficient other cancers were 71% and 67%, respectively. In MMR-proficient CRC, irORR and irPFS at 20 weeks were 0% and 11%, respectively. Response rates and Disease Control Rates (CR+PR+SD) by RECIST criteria were 40% and 90% in MMR-deficient CRC, 0% and 11% in MMR-proficient CRC, and 71% and 71% in MMR-deficient other cancers, respectively. Median PFS and overall survival (OS) were not reached in the MMR-deficient CRC group but was 2.2 and 5.0 months in the MMR-proficient CRC cohort (HR for PFS = 0.103; 95% CI, 0.029 to 0.373; p < 0.001 and HR for OS = 0.216; 95% CI, 0.047 to 1.000; p = 0.05). Whole exome sequencing revealed an average of 1,782 somatic mutations per tumor in MMR-deficient compared to 73 in MMR-proficient tumors (p = 0.0015), and high total somatic mutation loads were associated with PFS (p = 0.02). Conclusions: MMR status predicts clinical benefit of immune checkpoint blockade with pembrolizumab. Clinical trial information: NCT01876511.

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DNA damage response (DDR) gene mutations (mut), mut load, and sensitivity to chemotherapy plus immune checkpoint blockade in urothelial cancer (UC).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.300 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 300-300 ◽

Cited By ~ 4

Author(s):

Matt D. Galsky ◽

Andrew V. Uzilov ◽

Russell Bailey McBride ◽

Huan Wang ◽

Vaibhav G. Patel ◽

...

Keyword(s):

Exome Sequencing ◽

Immune Checkpoint ◽

Predictive Value ◽

Objective Response ◽

Gene Mutations ◽

Progression Free Survival ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Response To Treatment ◽

Cd8 Cells

300 Background: Somatic mut in DDR genes have been associated with increased sensitivity to cisplatin in UC. Higher mut load has correlated with response to immune checkpoint blockade. We hypothesized that DDR mut result in higher mut load and DDR mut UC may be particularly sensitive to both chemotherapy and immune checkpoint blockade. Methods: Three cohorts were utilized: (1) TCGA UC cohort (n = 389), (2) Mount Sinai (MS) cohort (n = 67) of UC (cystectomy) specimens subjected to targeted exome sequencing for 341 genes (MSK-IMPACT), and (3) Phase 2 trial of gemcitabine, cisplatin, plus ipilimumab (GCI) in metastatic UC from which 28/36 enrolled patients (pts) had specimens suitable for whole exome sequencing. DDR mut were defined as somatic alterations in one of 52 genes. Deleterious (del) mut were defined as nonsense, frameshift, splice site, or hotspot point mut. Results: The mut load using all genes in the TCGA cohort, and restricted to the 341 IMPACT genes, were highly correlated (rs= 0.81, p < 0.001). Associations between del DDR mut and mut load are shown (Table). In the MS cohort, CD8+cells/mm2 by IHC were higher in tumors with del DDR mut versus no DDR mut (p = 0.04). In the GCI cohort, the sensitivity, specificity, positive predictive value, and negative predictive value of a del DDR mut for objective response to treatment was 40.9% (95% CI 20.7-63.7%), 86.7% (95% CI 42.1-99.4%), 90% (55.5-99.8%), and 31.6% (95% CI 12.6-56.6%), respectively. Median progression-free survival in the GCI cohort was 308 days (95% CI 270-NR) in del DDR mut and 196 days (95% CI 185-372) in others (p = 0.24). Notably, 2/9 pts with del DDR mutations, and with the highest mut loads, achieved complete responses after GCI and are alive without evidence of disease at 2.1+ and 1.8+ years. Conclusions: DDR mut are associated with higher mut load in UC, a high likelihood of response to GCI, and may identify a subset of pts achieving durable disease control. GC plus PD-1/PD-L1 blockade should be explored in DDR mut UC. Clinical trial information: NCT01524991. [Table: see text]

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Multiparametric MRI of Early Tumor Response to Immune Checkpoint Blockade in Metastatic Melanoma

10.1101/2021.05.13.21257127 ◽

2021 ◽

Author(s):

Doreen Lau ◽

Mary A McLean ◽

Andrew N Priest ◽

Andrew B Gill ◽

Francis Scott ◽

...

Keyword(s):

Early Detection ◽

Metastatic Melanoma ◽

Immune Checkpoint ◽

Tumor Heterogeneity ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Immune Checkpoint Blockade ◽

Multiparametric Mri ◽

Checkpoint Blockade ◽

Tumor Cell Death

Background: Immune checkpoint inhibitors are now standard of care treatment for many cancers. Treatment failure in metastatic melanoma is often due to tumor heterogeneity not easily captured by conventional CT or tumor biopsy. The aim of this prospective study was to investigate early microstructural and functional changes within melanoma metastases following immune checkpoint blockade using multiparametric MRI. Methods: Fifteen treatment-naïve metastatic melanoma patients (total 27 measurable target lesions) were imaged at baseline, and following three weeks and twelve weeks of treatment on immune checkpoint inhibitors using T2-weighted imaging, diffusion kurtosis imaging and dynamic contrast-enhanced MRI. Treatment timepoint changes in tumor cellularity, vascularity and heterogeneity within individual metastases were evaluated and correlated to the clinical outcome within each patient. Results: Differential tumor growth kinetics in response to immune checkpoint blockade were measured in individual metastases within the same patient. Early detection of tumor cell death or cell loss measured by a significant increase in the apparent diffusivity Dapp (p < 0.05) was observed in both responding and pseudoprogressive lesions after three week of treatment. Tumor heterogeneity (apparent kurtosis Kapp) was consistently higher in the pseudoprogressive and true progressive lesions, compared to the responding lesions throughout the first twelve weeks of treatment. These preceded tumor regression and significant tumor vascularity changes (Ktrans, ve and vp) detected after twelve weeks of immunotherapy (p < 0.05). Conclusions: Multiparametric MRI demonstrated potential for early detection of successful response to immunotherapy in metastatic melanoma.

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Multiparametric MRI of early tumor response to immune checkpoint blockade in metastatic melanoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-003125 ◽

2021 ◽

Vol 9 (9) ◽

pp. e003125 ◽

Cited By ~ 1

Author(s):

Doreen Lau ◽

Mary A McLean ◽

Andrew N Priest ◽

Andrew B Gill ◽

Francis Scott ◽

...

Keyword(s):

Early Detection ◽

Metastatic Melanoma ◽

Immune Checkpoint ◽

Tumor Heterogeneity ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Immune Checkpoint Blockade ◽

Multiparametric Mri ◽

Checkpoint Blockade ◽

Tumor Cell Death

BackgroundImmune checkpoint inhibitors are now standard of care treatment for many cancers. Treatment failure in metastatic melanoma is often due to tumor heterogeneity, which is not easily captured by conventional CT or tumor biopsy. The aim of this prospective study was to investigate early microstructural and functional changes within melanoma metastases following immune checkpoint blockade using multiparametric MRI.MethodsFifteen treatment-naïve metastatic melanoma patients (total 27 measurable target lesions) were imaged at baseline and following 3 and 12 weeks of treatment on immune checkpoint inhibitors using: T2-weighted imaging, diffusion kurtosis imaging, and dynamic contrast-enhanced MRI. Treatment timepoint changes in tumor cellularity, vascularity, and heterogeneity within individual metastases were evaluated and correlated to the clinical outcome in each patient based on Response Evaluation Criteria in Solid Tumors V.1.1 at 1 year.ResultsDifferential tumor growth kinetics in response to immune checkpoint blockade were measured in individual metastases within the same patient, demonstrating significant intertumoral heterogeneity in some patients. Early detection of tumor cell death or cell loss measured by a significant increase in the apparent diffusivity (Dapp) (p<0.05) was observed in both responding and pseudoprogressive lesions after 3 weeks of treatment. Tumor heterogeneity, as measured by apparent diffusional kurtosis (Kapp), was consistently higher in the pseudoprogressive and true progressive lesions, compared with the responding lesions throughout the first 12 weeks of treatment. These preceded tumor regression and significant tumor vascularity changes (Ktrans, ve, and vp) detected after 12 weeks of immunotherapy (p<0.05).ConclusionsMultiparametric MRI demonstrated potential for early detection of successful response to immune checkpoint inhibitors in metastatic melanoma.

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Burden of copy number alterations predicts outcomes in immune checkpoint blockade treated gastrointestinal cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14068 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14068-e14068

Author(s):

Zhihao Lu ◽

Huan Chen ◽

Shuang Li ◽

Xi Jiao ◽

Lihong Wu ◽

...

Keyword(s):

Immune Checkpoint ◽

Copy Number ◽

Objective Response ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Copy Number Alterations ◽

Sequencing Platform ◽

Gi Cancer ◽

Ffpe Tumor ◽

Gi Cancers

e14068 Background: Despite the great achievements made in immune checkpoint blockade (ICB) in cancer therapy, how to identify patients who may benefit from ICB still remains one of the central questions, especially in gastrointestinal (GI) cancer. Methods: To address this, we analyzed FFPE tumor specimens from 73 patients with metastatic GI cancers who were treated with ICB. All patients were randomly assigned into discovery (60%) and validation (40%) cohorts. Overall, tumor mutation burden (TMB) and copy number alterations (CNAs) were determined by using the whole-exome sequencing platform. FFPE samples of 65 patients were analyzed via a multiplex RNA immune oncology sequencing panel. Results: Here we show that lower burden of copy number alteration (CNA) was observed in responders to immunotherapy in both discovery and validation cohorts. More importantly, lower burden of CNA in GI cancers were associated with improved objective response, clinical benefit and overall survival. Efficacy also correlated with the higher TMB. Of note, a combinatorial biomarker of TMB and burden of CNA may better stratify responders from patients received immunotherapy. In addition, patients with lower burden of CNA revealed increased IFNγ and expanded immune signatures in our GI patient cohort and TCGA cohorts as well. Conclusions: Our results suggest that burden of CNA may expand the predictive and prognostic value of genomic determinants in identifying potential responders with GI cancer to immune checkpoint blockade therapy.

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