Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy
Abstract
Advanced colorectal cancer is one of the deadliest cancers, with a 5-year survival rate of only 12% for patients with the metastatic disease. Checkpoint inhibitors, such as the antibodies inhibiting the PD-1/PD-L1 axis, are among the most promising immunotherapies for patients with advanced colon cancer, but their durable response rate remains low. We herein report the use of immunogenic nanoparticles to augment the antitumour efficacy of PD-L1 antibody-mediated cancer immunotherapy. Nanoscale coordination polymer (NCP) core-shell nanoparticles carry oxaliplatin in the core and the photosensitizer pyropheophorbide-lipid conjugate (pyrolipid) in the shell (NCP@pyrolipid) for effective chemotherapy and photodynamic therapy (PDT). Synergy between oxaliplatin and pyrolipid-induced PDT kills tumour cells and provokes an immune response, resulting in calreticulin exposure on the cell surface, antitumour vaccination and an abscopal effect. When combined with anti-PD-L1 therapy, NCP@pyrolipid mediates regression of both light-irradiated primary tumours and non-irradiated distant tumours by inducing a strong tumour-specific immune response.
https://www.nature.com/articles/ncomms12499
Core shell nanoscale coordination polymers combine chemotherapy & photodynamic therapy to potentiate checkpoint blockad
Core shell nanoscale coordination polymers combine chemotherapy & photodynamic therapy to potentiate checkpoint blockad
Last edited by D.ap on Thu Nov 28, 2019 10:54 am, edited 5 times in total.
Debbie
Re: Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint bl
Introduction
Approximately 150,000 patients are diagnosed with colorectal cancer in the United States annually, with one-third dying from metastasis1. Although the 5-year survival rate for localized colorectal cancer is ∼89%, this number drops to only ∼12% for cancers that have metastasized to the liver, lungs or peritoneum2.
Stimulation of the host immune system has been shown to generate an antitumour immune response capable of controlling metastatic tumour growth3,4,5,6. Immune checkpoint blockade therapy, which targets regulatory pathways in T cells to enhance antitumour immune response, has witnessed significant clinical advances and provided a new strategy to combat cancer7. Among them, the PD-1/PD-L1 pathway inhibits immune activation by suppressing effector T-cell function8,9 and is upregulated in many tumours to cause apoptosis of tumour-specific cytotoxic T-lymphocytes and transmit an anti-apoptotic signal to tumour cells10,11. Antibody-mediated specific blockade of the PD-1/PD-L1 axis can generate potent antitumour activity in murine tumour models12,13. With the exception of metastatic melanoma, the durable responses generated by checkpoint blockade therapy are still low. Although blockade of PD-1 was shown not to be effective in metastatic colon cancer, a recent report by Le et al.14 demonstrated that PD-1 blockade was effective in a subset of colon cancer patients who were deficient in mismatch repair, reopening the door to immune modulation with interventions such as chemotherapy and radiotherapy to increase the durable response rate15. We hypothesize that combining PD-L1 blockade with multimodality nanoscale coordination polymer (NCP) nanoparticles can increase the response rate of checkpoint blockade cancer immunotherapy and perhaps broaden the use of immunotherapy in metastatic colon cancer.
As a new class of self-assembled hybrid nanomaterials composed of metal connecting points and organic bridging ligands16,17, NCPs have highly tunable compositions and structures, can combine multiple therapeutic agents or modalities18 and are intrinsically biodegradable. By combining non-toxic photosensitizers, light and oxygen to produce cytotoxic reactive oxygen species, in particular singlet oxygen (1O2), photodynamic therapy (PDT) kills cancer cells by apoptosis and necrosis, stimulates the host immune system and causes acute inflammation and leukocyte infiltration to the tumours, which increases the presentation of tumour-derived antigens to T cells19,20,21,22,23,24,25. Oxaliplatin was shown to induce immunogenic cell death (ICD) in murine colorectal cancer models26.
We herein report the design of NCP nanoparticles that carry oxaliplatin and the photosensitizer pyrolipid (NCP@pyrolipid), to significantly enhance antitumour immunity. NCP@pyrolipid combines two therapeutic modalities, chemotherapy and PDT, to elicit antitumour immunity27,28,29, as evidenced by early calreticulin (CRT) exposure on the cell surface, antitumour vaccination, tumour-specific T-cell response and an abscopal effect. The abscopal effect is usually described with ionizing radiation and refers to regression of tumour outside of the irradiated volume. Although the mechanism is unknown, it is thought to be immune modulated. More importantly, NCP@pyrolipid PDT treatment in combination with PD-L1 checkpoint blockade therapy not only led to the regression of the primary tumours, treated locally with light irradiation, but also resulted in the regression of the distant tumours in bilateral syngeneic mouse tumour models of CT26 and MC38 by generating systemic tumour-specific T-cell response with the infiltration of CD8+ T cells and CD4+ T cells in distant tumours.
Approximately 150,000 patients are diagnosed with colorectal cancer in the United States annually, with one-third dying from metastasis1. Although the 5-year survival rate for localized colorectal cancer is ∼89%, this number drops to only ∼12% for cancers that have metastasized to the liver, lungs or peritoneum2.
Stimulation of the host immune system has been shown to generate an antitumour immune response capable of controlling metastatic tumour growth3,4,5,6. Immune checkpoint blockade therapy, which targets regulatory pathways in T cells to enhance antitumour immune response, has witnessed significant clinical advances and provided a new strategy to combat cancer7. Among them, the PD-1/PD-L1 pathway inhibits immune activation by suppressing effector T-cell function8,9 and is upregulated in many tumours to cause apoptosis of tumour-specific cytotoxic T-lymphocytes and transmit an anti-apoptotic signal to tumour cells10,11. Antibody-mediated specific blockade of the PD-1/PD-L1 axis can generate potent antitumour activity in murine tumour models12,13. With the exception of metastatic melanoma, the durable responses generated by checkpoint blockade therapy are still low. Although blockade of PD-1 was shown not to be effective in metastatic colon cancer, a recent report by Le et al.14 demonstrated that PD-1 blockade was effective in a subset of colon cancer patients who were deficient in mismatch repair, reopening the door to immune modulation with interventions such as chemotherapy and radiotherapy to increase the durable response rate15. We hypothesize that combining PD-L1 blockade with multimodality nanoscale coordination polymer (NCP) nanoparticles can increase the response rate of checkpoint blockade cancer immunotherapy and perhaps broaden the use of immunotherapy in metastatic colon cancer.
As a new class of self-assembled hybrid nanomaterials composed of metal connecting points and organic bridging ligands16,17, NCPs have highly tunable compositions and structures, can combine multiple therapeutic agents or modalities18 and are intrinsically biodegradable. By combining non-toxic photosensitizers, light and oxygen to produce cytotoxic reactive oxygen species, in particular singlet oxygen (1O2), photodynamic therapy (PDT) kills cancer cells by apoptosis and necrosis, stimulates the host immune system and causes acute inflammation and leukocyte infiltration to the tumours, which increases the presentation of tumour-derived antigens to T cells19,20,21,22,23,24,25. Oxaliplatin was shown to induce immunogenic cell death (ICD) in murine colorectal cancer models26.
We herein report the design of NCP nanoparticles that carry oxaliplatin and the photosensitizer pyrolipid (NCP@pyrolipid), to significantly enhance antitumour immunity. NCP@pyrolipid combines two therapeutic modalities, chemotherapy and PDT, to elicit antitumour immunity27,28,29, as evidenced by early calreticulin (CRT) exposure on the cell surface, antitumour vaccination, tumour-specific T-cell response and an abscopal effect. The abscopal effect is usually described with ionizing radiation and refers to regression of tumour outside of the irradiated volume. Although the mechanism is unknown, it is thought to be immune modulated. More importantly, NCP@pyrolipid PDT treatment in combination with PD-L1 checkpoint blockade therapy not only led to the regression of the primary tumours, treated locally with light irradiation, but also resulted in the regression of the distant tumours in bilateral syngeneic mouse tumour models of CT26 and MC38 by generating systemic tumour-specific T-cell response with the infiltration of CD8+ T cells and CD4+ T cells in distant tumours.
Debbie
Re: Core shell nanoscale coordination polymers combine chemotherapy & photodynamic therapy to potentiate checkpoint bloc
Cont..
Immunoprofiling in alveolar soft part sarcoma.
Background: Alveolar Soft Part Sarcoma (ASPS) is a distinctive tumor characterized by a canonical ASPL-TFE3 fusion. Treatment options are limited. We assessed tumor immune cell infiltrates, and correlated this with patients receiving PD-1 blockade. Methods: A retrospective institutional review was performed for 18 cases of ASPS. Immunohistochemistry was performed on paraffin-embedded tissue (PET) for T-lymphocyte markers (CD3/CD4/CD8), and PD-1/PD-L1 (Ventana). Expression was quantified by standard methods: (total cells per high power field: score; 0:0; 1-10:1; 11-50:2; 50-99:3; 100:4). Select cases underwent DNA sequencing analysis using whole exome (WES, > 80X, n = 4) and genome (WGS, > 30X, n = 1) sequencing. Indel analysis was conducted via mutect2 ( > 5% variant allele frequency) and mutational signature was performed using deconstructSigs. Results: The median age was 27 (15-54). Disease status at diagnosis was: 44% localized; 56% metastatic. The median overall survival was 17 yrs (2.9-31). Four patients (pts) received immunotherapy with PD-1 blockade with 1 complete response (CR), 2 durable partial responses (PR) and 1 stable disease (SD). PET was available in 12 cases. PD-1/PD-L1 expression (≥1) was seen in 50% and 17%, respectively. Composite CD3, CD4 and CD8 infiltration were 2, 1, and 1, respectively. Patients with CR/PR to PD-1 blockade (n = 3) had no clear correlation with PD-1, PD-L1 or lymphocyte markers. Exomic characterization (n = 4) demonstrated no clear excess mutation burden compared to Ewing sarcoma (5.7 vs 6.4 mut/MB). Mutational signatures via COSMIC were identified in the mismatch repair (MMR) pathway in 2 of 4 cases (Pt A: Signature (S) 26; pt B: S6 and S15). Pt B also underwent WGS which confirmed a COSMIC signature in the MMR pathway. Indel analysis did not confirm aberrations in standard MMR or polymerase genes. Conclusions: Preliminary findings suggest activity with PD-1 blockade in ASPS; however, this does not appear to correlate with tumour-infiltrating T lymphocytes. Genomic analysis suggests an MMR signature may account for these responses, but standard MMR aberrations were not identified. Further validation is underway.
https://ascopubs.org/doi/abs/10.1200/JC ... uppl.11059
Immunoprofiling in alveolar soft part sarcoma.
Background: Alveolar Soft Part Sarcoma (ASPS) is a distinctive tumor characterized by a canonical ASPL-TFE3 fusion. Treatment options are limited. We assessed tumor immune cell infiltrates, and correlated this with patients receiving PD-1 blockade. Methods: A retrospective institutional review was performed for 18 cases of ASPS. Immunohistochemistry was performed on paraffin-embedded tissue (PET) for T-lymphocyte markers (CD3/CD4/CD8), and PD-1/PD-L1 (Ventana). Expression was quantified by standard methods: (total cells per high power field: score; 0:0; 1-10:1; 11-50:2; 50-99:3; 100:4). Select cases underwent DNA sequencing analysis using whole exome (WES, > 80X, n = 4) and genome (WGS, > 30X, n = 1) sequencing. Indel analysis was conducted via mutect2 ( > 5% variant allele frequency) and mutational signature was performed using deconstructSigs. Results: The median age was 27 (15-54). Disease status at diagnosis was: 44% localized; 56% metastatic. The median overall survival was 17 yrs (2.9-31). Four patients (pts) received immunotherapy with PD-1 blockade with 1 complete response (CR), 2 durable partial responses (PR) and 1 stable disease (SD). PET was available in 12 cases. PD-1/PD-L1 expression (≥1) was seen in 50% and 17%, respectively. Composite CD3, CD4 and CD8 infiltration were 2, 1, and 1, respectively. Patients with CR/PR to PD-1 blockade (n = 3) had no clear correlation with PD-1, PD-L1 or lymphocyte markers. Exomic characterization (n = 4) demonstrated no clear excess mutation burden compared to Ewing sarcoma (5.7 vs 6.4 mut/MB). Mutational signatures via COSMIC were identified in the mismatch repair (MMR) pathway in 2 of 4 cases (Pt A: Signature (S) 26; pt B: S6 and S15). Pt B also underwent WGS which confirmed a COSMIC signature in the MMR pathway. Indel analysis did not confirm aberrations in standard MMR or polymerase genes. Conclusions: Preliminary findings suggest activity with PD-1 blockade in ASPS; however, this does not appear to correlate with tumour-infiltrating T lymphocytes. Genomic analysis suggests an MMR signature may account for these responses, but standard MMR aberrations were not identified. Further validation is underway.
https://ascopubs.org/doi/abs/10.1200/JC ... uppl.11059
Debbie