RESUMO
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic options. IL1 receptor type 2 (IL1R2) promotes breast tumor-initiating cell (BTIC) self-renewal and tumor growth in TNBC, indicating that targeting it could improve patient treatment. In this study, we observed that IL1R2 blockade strongly attenuated macrophage recruitment and the polarization of tumor-associated macrophages (TAM) to inhibit BTIC self-renewal and CD8+ T-cell exhaustion, which resulted in reduced tumor burden and prolonged survival in TNBC mouse models. IL1R2 activation by TAM-derived IL1ß increased PD-L1 expression by interacting with the transcription factor Yin Yang 1 (YY1) and inducing YY1 ubiquitination and proteasomal degradation in both TAMs and TNBC cells. Loss of YY1 alleviated the transcriptional repression of c-Fos, which is a transcriptional activator of PDL-1. Combined treatment with an IL1R2-neutralizing antibodies and anti-PD-1 led to enhanced antitumor efficacy and reduced TAMs, BTICs, and exhausted CD8+ T cells. These results suggest that IL1R2 blockade might be a strategy to potentiate immune checkpoint blockade efficacy in TNBC to improve patient outcomes. Significance: IL1R2 in both macrophages and breast cancer cells orchestrates an immunosuppressive tumor microenvironment by upregulating PD-L1 expression and can be targeted to enhance the efficacy of anti-PD-1 in triple-negative breast cancer.
Assuntos
Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Camundongos , Humanos , Feminino , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/efeitos dos fármacos , Linhagem Celular Tumoral , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Fator de Transcrição YY1/metabolismo , Fator de Transcrição YY1/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/efeitos dos fármacosRESUMO
OBJECTIVE: In China, grade 2 to 3 immune-related rash will probably lead to the interruption of immunotherapy. Corticosteroid (CS) is the main treatment, but not always effective. The external application of clearing heat and removing dampness, which is represented by Qing-Re-Li-Shi Formula (QRLSF), has been used in our hospital to treat immune-related cutaneous adverse events (ircAEs) for the last 5 years. The purpose of this study was to discuss its efficacy and safety in the treatment of grade 2 to 3 rash. METHODS: A retrospective study of patients with grade 2 to 3 immune-related rash in our hospital from December 2019 to December 2022 was conducted. These patients received QRLSF treatment. Clinical characteristics, treatment outcome, and health-related quality of life (HrQoL) were analyzed. RESULTS: Thirty patients with grade 2 to 3 rash (median onset time: 64.5 days) were included. The skin lesions of 24 cases (80%) returned to grade 1 with a median time of 8 days. The accompanying symptoms were also improved with median time of 3 to 4 days. The addition of antihistamine (AH) drug didn't increase the efficacy of QRLSF (AH + QRLSF: 75.00% vs QRLSF: 83.33%, P = .66). No significant difference was observed in the efficacy of QRLSF treatment regardless of whether patients had previously received CS therapy (untreated population: 88.24% vs treated population: 69.23%, P = .36). During 1-month follow-up, 2 cases (8.33%) underwent relapses. In terms of HrQoL, QRLSF treatment could significantly reduce the median scores of all domains of Skindex-16, including symptoms (39.58 vs 8.33, P < .0001), emotions (58.33 vs 15.48, P < .0001), functioning (46.67 vs 13.33, P < .0001) and composite (52.60 vs 14.06, P < .0001). CONCLUSION: External application of clearing heat and removing dampness was proven to be an effective and safe treatment for such patients. In the future, high-quality trials are required to determine its clinical application in the field of ircAEs.
Assuntos
Antígeno B7-H1 , Exantema , Receptor de Morte Celular Programada 1 , Humanos , Antígeno B7-H1/antagonistas & inibidores , Exantema/induzido quimicamente , Exantema/tratamento farmacológico , Temperatura Alta , Ligantes , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Qualidade de Vida , Estudos RetrospectivosRESUMO
BACKGROUND: The repression or downregulation of programmed death-ligand 1 (PD-L1) can release its inhibition of T cells and activate antitumor immune responses. Although PD-1 and PD-L1 antibodies are promising treatments for diverse tumor types, their inherent disadvantages and immune-related adverse events remain significant issues. The development of small molecule inhibitors targeting the interaction surface of PD-1 and PD-L1 has been reviving, yet many challenges remain. To address these issues, we aimed to find small molecules with durable efficacy and favorable biosafety that alter PD-L1 surface expression and can be developed into a promising alternative and complementary therapy for existing anti-PD-1/PD-L1 therapies. METHODS: Cell-based screen of 200 metabolic molecules using a high-throughput flow cytometry assay of PD-L1 surface expression was conducted, and L-5-hydroxytryptophan (L-5-HTP) was found to suppress PD-L1 expression induced by interferon gamma (IFN-γ). Inhibition of PD-L1 induction and antitumor effect of L-5-HTP were evaluated in two syngeneic mouse tumor models. Flow cytometry was performed to investigate the change in the tumor microenvironment caused by L-5-HTP treatment. RESULTS: We discovered that L-5-HTP suppressed IFN-γ-induced PD-L1 expression in tumor cells transcriptionally, and this effect was directly due to itself. Mechanistically, L-5-HTP inhibited IFN-γ-induced expression of RTK ligands and thus suppressed phosphorylation-mediated activation of RTK receptors and the downstream MEK/ERK/c-JUN signaling cascade, leading to decreased PD-L1 induction. In syngeneic mouse tumor models, treatment with 100 mg/kg L-5-HTP (intraperitoneal) inhibited PD-L1 expression and exhibited antitumor effect. L-5-HTP upregulated the ratio of granzyme B+ CD8+ activated cytotoxic T cells. An intact immune system and PD-L1 expression was critical for L-5-HTP to exert its antitumor effects. Furthermore, L-5-HTP acted synergistically with PD-1 antibody to improve anticancer effect. CONCLUSION: Our study illustrated L-5-HTP's inhibitory effect on PD-L1 induction stimulated by IFN-γ in tumor cells and also provided insight into repurposing L-5-HTP for use in tumor immunotherapy.
Assuntos
5-Hidroxitriptofano , Antígeno B7-H1 , Receptor de Morte Celular Programada 1 , 5-Hidroxitriptofano/farmacologia , Animais , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Humanos , Interferon gama/metabolismo , Camundongos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/biossíntese , Receptor de Morte Celular Programada 1/imunologiaRESUMO
BACKGROUND: Vascular endothelial growth factor (VEGF) plays a role in the tumor microenvironment. Sorafenib, which inhibits the VEGF pathway, has an immune-modulation function but lacks substantial clinical data. This study aims to explore the efficacy of anti-PD-1 combined sorafenib in advanced hepatocellular carcinoma (HCC). METHODS: HCC patients who underwent anti-PD-1 treatment at Taipei Veterans General Hospital (Taipei, Taiwan) between January 2016 and February 2019 were reviewed. The efficacy was compared between groups after propensity-score matching. RESULTS: There were 173 HCC patients receiving anti-PD-1. After excluding unsuitable cases, 140 patients were analyzed, of which 58 received combination therapy and 82 received anti-PD-1 alone. The combination therapy had a trend of higher CR rate (8.6% vs. 4.9%, ns.), ORR (22.4% vs. 19.5%, ns.) and significantly higher DCR (69.0% vs. 37.8%, p < 0.05) comparing to anti-PD-1 alone. After matching, combination group achieved longer progression-free survival (3.87 vs. 2.43 months, p < 0.05) and overall survival (not reached vs. 7.17 months, p < 0.05) than anti-PD-1 alone, without higher grade 3/4 AE (10.3% vs. 7.1%, p = 0.73). The tumor response varied among different metastatic sites, with high responses in adrenal glands, peritoneum and lungs. The more AFP declined (> 10, > 50 and > 66%), the higher the ORR (70, 80 and 92%) and CR rates (30, 35 and 58%) were achieved at day 28. CONCLUSIONS: This is the first study to demonstrate the combination of anti-PD-1 and sorafenib had better efficacy and survival benefit. A prospective randomized study is needed to confirm this finding.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Hepáticas , Sorafenibe/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Quimioterapia Combinada , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Pontuação de Propensão , Estudos RetrospectivosRESUMO
BACKGROUND: Limited data exist on safe discontinuation of antiprogrammed cell death protein 1 (PD-1) therapy in responding patients with advanced melanoma. The use of 18fluorodeoxyglucose (18FDG)-PET/CT scan and tumor biopsy for assessment of active disease may be an effective predictive biomarker to guide such treatment decisions. METHODS: A retrospective study of 122 patients with advanced melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anticytotoxic T-lymphocyte-associated protein 4 combination therapy at Georgetown Lombardi Comprehensive Cancer Center was conducted. Uveal melanoma patients and those receiving concurrent experimental therapy were excluded. Baseline characteristics, treatment outcomes, and survival were analyzed. Patients who decided to come off treatment typically after 12 months using CT scan radiographic complete response (CR), 18FDG-PET/CT scan complete metabolic response (CMR) or tumor biopsy of a non-CR/CMR tumor site negative for active disease (possible pathological CR) were identified and compared with patients who discontinued treatment due to toxicity while their disease was in control. Event-free survival (EFS) was assessed from the last dose of anti-PD-1 therapy to progression requiring subsequent treatment (surgery, radiation, and/or systemic therapy) or referral to hospice/death due to melanoma. RESULTS: 24 (20%) patients discontinued treatment by choice with no active disease and 28 (23%) patients discontinued treatment due to toxicity with disease control after 12-month and 4-month median treatment durations, respectively. Similar baseline characteristics were observed between cohorts except higher prior receipt of ipilimumab (29% vs 7%; p=0.036) and fewer BRAF mutant positive disease (17% vs 41%; p=0.064) in patients off treatment by choice. Three-year EFS rates were 95% and 71%, respectively. No significant associations between EFS and sex, disease stage, lactate dehydrogenase elevation, BRAF status, prior systemic therapy, ECOG performance status, presence of brain metastases, or combination versus monotherapy were observed. Tumor biopsies led to alternative management in 3/10 patients due to active metastatic melanoma or second malignancy. CONCLUSIONS: Anti-PD-1 therapy discontinuation after 12 months when no active disease is observed on CT scan, PET/CT scan or tumor biopsy may have low rates of disease relapse in patients with advanced melanoma. Biopsy of residual disease may frequently lead to a change in management. These findings are undergoing validation in the EA6192 trial.
Assuntos
Biópsia/métodos , Imunoterapia/métodos , Melanoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Feminino , Humanos , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Immune checkpoints such as programmed death-1 (PD-1) have been proven as antitumor targets by enhancing cytotoxic T cell activity. All immune checkpoint blockades are antibody therapeutics that have large size and high affinity, as well as known immune-related side effects and low responses. To overcome the limitation of antibody therapeutics, we have explored PD-1/PD-L1 (programmed death-ligand 1) blockades in traditional oriental medicine, which has a long history but has not yet studied PD-1/PD-L1 blockades. Sanguisorbae Radix extract (SRE) blocked PD-1 and PD-L1 binding in competitive ELISA. SRE effectively inhibited the PD-1/PD-L1 interaction, thereby improving T cell receptor (TCR) signaling and the NFAT-mediated luciferase activity of T cells. SRE treatment reduced tumor growth in the humanized PD-L1 MC38 cell allograft humanized PD-1 mouse model. Additionally, the combination of SRE and pembrolizumab (anti-PD-1 antibody) suppressed tumor growth and increased infiltrated cytotoxic T cells to a greater extent did either agent alone. This study showed that SRE alone has anticancer effects via PD-1/PD-L1 blockade and that the combination therapy of SRE and pembrolizumab has enhanced immuno-oncologic effects.
Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/farmacologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Extratos Vegetais/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Sanguisorba , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Células CHO , Técnicas de Cocultura , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Cricetulus , Humanos , Células Jurkat , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Extratos Vegetais/isolamento & purificação , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Sanguisorba/química , Transdução de Sinais , Carga TumoralRESUMO
Background: The pathogenesis of thyroiditis caused by immune-checkpoint inhibitors (ICIs) such as antiprogrammed death receptor-1 (PD-1) and anticytotoxic T lymphocyte antigen-4 (CTLA-4) is incompletely understood. To gain mechanistic insights, we developed a mouse model of ICI-related thyroiditis and assessed the clinical, hormonal, and cytokine profiles. Methods: Forty NOD-H2h4 mice, 112 days old at the start of the experiments, were divided into two sequential cohorts. In the first one (No. = 21), mice were injected with both anti-PD-1 and anti-CTLA-4 checkpoint inhibitors while drinking either regular water or iodine-supplemented water. In the second cohort (No. = 19), mice were injected with either anti-PD-1 or anti-CTLA-4 while drinking iodine-supplemented water. Mice were sacrificed two months after the initial injection to collect thyroid gland for histopathology (to assess thyroiditis severity) and flow cytometry (to identify immune cell subsets and tissue-resident memory T cell markers). Mice were also studied before sacrifice to determine thyroid area and structure (by ultrasound), thyroid function (serum total thyroxine, thyrotropin, thyroid antibodies), and cytokine profile (by bead-based Luminex technology). Results: Thyroiditis was more severe upon PD-1 than CTLA-4 blockade (p = 0.01) and significantly correlated with the number of CD45+ cells infiltrating the thyroid (cumulative odds ratio [OR] 1.2 [95% confidence interval, CI 1.1-1.3], p < 0.001, that is 20% greater odds of a higher severity score for every 170-unit increase in CD45 infiltrating cells). Thyroiditis was instead more prevalent (100% vs. 63%, p < 0.01) in the anti-CTLA-4 mice, which also showed a larger thyroid area (17 ± 8.2 mm) than those treated with anti-PD-1 (11 ± 4.2 mm) and controls (p < 0.01). Serum IL-6 was markedly increased upon PD-1 blockade (40 pg/mL at baseline, 198 pg/mL on day 172), an increase not seen in the anti-CTLA-4 group (p = 0.01). IL-6 mirrored thyroiditis severity, with highest serum values found in greatest histopathology scores (cumulative OR 1.1 [CI 1.02-1.15], p = 0.009). GM-CSF and MIP1ß increased more in the anti-CTLA-4 group (p < 0.001 for both), whereas the other cytokines did not differ among the treatment groups. Conclusions: The study reports a mouse model of thyroiditis induced by PD-1 blockade and, comparing it to the anti-CTLA-4 model, uncovers distinctive histopathological, sonographic, hormonal, and immunological features, offering biomarkers, such as serum IL-6, that could be used in the clinical setting.
Assuntos
Antígeno CTLA-4/antagonistas & inibidores , Citocinas/sangue , Inibidores de Checkpoint Imunológico/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Tireoidite Autoimune/imunologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos Endogâmicos NODRESUMO
The response rate of anti-PD therapy in most cancer patients remains low. Therapeutic drug and tumor-infiltrating lymphocytes (TILs) are usually obstructed by the stromal region within tumor microenvironment (TME) rather than distributed around tumor cells, thus unable to induce the immune response of cytotoxic T cells. Here, we constructed the cationic thermosensitive lipid nanoparticles IR780/DPPC/BMS by introducing cationic NIR photosensitizer IR-780 iodide (IR780) modified lipid components, thermosensitive lipid DPPC and PD-1/PD-L1 inhibitor BMS202 (BMS). Upon laser irradiation, IR780/DPPC/BMS penetrated into deep tumor, and reduced cancer-associated fibroblasts (CAFs) around tumor cells to remodel the spatial distribution of TILs in TME. Interestingly, the cationic IR780/DPPC/BMS could capture released tumor-associated antigens (TAAs), thereby enhancing the antigen-presenting ability of DCs to activate cytotoxic T lymphocytes. Moreover, IR780/DPPC/BMS initiated gel-liquid crystal phase transition under laser irradiation, accelerating the disintegration of lipid bilayer structure and leading to the responsive release of BMS, which would reverse the tumor immunosuppression state by blocking PD-1/PD-L1 pathway for a long term. This combination treatment can synergistically exert the antitumor immune response and inhibit the tumor growth and metastasis.
Assuntos
Antígeno B7-H1/imunologia , Lipossomos/farmacologia , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/imunologia , Acetamidas/química , Acetamidas/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Tolerância Imunológica/efeitos dos fármacos , Imunoterapia/métodos , Indóis/química , Indóis/farmacologia , Lipossomos/química , Terapia com Luz de Baixa Intensidade , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos da radiação , Nanopartículas/química , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/radioterapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/efeitos da radiação , Microambiente Tumoral/efeitos dos fármacosRESUMO
YIV-906 (PHY906) is a standardized botanical cancer drug candidate developed with a systems biology approach-inspired by a traditional Chinese herbal formulation, historically used to treat gastrointestinal symptoms including diarrhea, nausea and vomiting. In combination with chemotherapy and/or radiation therapy, preclinical and clinical results suggest that YIV-906 has the potential to prolong survival and improve quality of life for cancer patients. Here, we demonstrated that YIV-906 plus anti-PD1 could eradicate all Hepa 1-6 tumors in all tumor bearing mice. YIV-906 was found to have multiple mechanisms of action to enhance adaptive and innate immunity. In combination, YIV-906 reduced PD1 or counteracted PD-L1 induction caused by anti-PD1 which led to higher T-cell activation gene expression of the tumor. In addition, YIV-906 could reduce immune tolerance by modulating IDO activity and reducing monocytic MDSC of the tumor. The combination of anti-PD1 and YIV-906 generated acute inflammation in the tumor microenvironment with more M1-like macrophages. YIV-906 could potentiate the action of interferon gamma (IFNg) to increase M1-like macrophage polarization while inhibiting IL4 action to decrease M2 macrophage polarization. Flavonoids from YIV-906 were responsible for modulating IDO activity and potentiating IFNg action in M1-like macrophage polarization. In conclusion, YIV-906 could act as an immunomodulator and enhance the innate and adaptive immune response and potentiate anti-tumor activity for immunotherapies to treat cancer.
Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Carcinoma Hepatocelular/imunologia , Medicamentos de Ervas Chinesas/farmacologia , Imunidade Inata/efeitos dos fármacos , Neoplasias Hepáticas/imunologia , Proteínas de Neoplasias/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral/efeitos dos fármacos , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Feminino , Neoplasias Hepáticas/dietoterapia , Camundongos , Proteínas de Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral/imunologiaRESUMO
Through specific structural modification of a 4-phenylindoline precursor, new 4-arylindolines containing a thiazole moiety were developed and found to be promising modulators of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis. Compound A30 exhibited outstanding biochemical activity, with an IC50 of 11.2 nM in a homogeneous time-resolved fluorescence assay. In the cell-based assay, A30 significantly promoted IFN-γ secretion and rescued T-cell proliferation, which were inhibited by PD-1 activation. Furthermore, A30 showed favorable in vivo antitumor activity in a mouse 4T1 breast carcinoma model. Moreover, in mouse CT26 colon carcinoma models, A30 potently suppressed the growth of CT26/PD-L1 tumor but did not obviously affect the growth of CT26/vector tumor. The results of flow cytometry analysis indicated that A30 inhibited tumor growth by activating the immune microenvironment. We concluded that A30 is a new starting point for further development of PD-1/PD-L1 interaction inhibitors as antitumor agents.
Assuntos
Antineoplásicos/química , Antígeno B7-H1/metabolismo , Indóis/química , Receptor de Morte Celular Programada 1/metabolismo , Tiazóis/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Indóis/metabolismo , Indóis/farmacologia , Indóis/uso terapêutico , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Mapas de Interação de Proteínas/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
BACKGROUND: PD-1/PD-L1 engagement and overexpression of galectin-3 (Gal-3) are critical mechanisms of tumor-induced immune suppression that contribute to immunotherapy resistance. We hypothesized that Gal-3 blockade with belapectin (GR-MD-02) plus anti-PD-1 (pembrolizumab) would enhance tumor response in patients with metastatic melanoma (MM) and head and neck squamous cell carcinoma (HNSCC). METHODS: We performed a phase I dose escalation study of belapectin+pembrolizumab in patients with advanced MM or HNSCC (NCT02575404). Belapectin was administered at 2, 4, or 8 mg/kg IV 60 min before pembrolizumab (200 mg IV every 3 weeks for five cycles). Responding patients continued pembrolizumab monotherapy for up to 17 cycles. Main eligibility requirements were a functional Eastern Cooperative Oncology Group status of 0-2, measurable or assessable disease, and no active autoimmune disease. Prior T-cell checkpoint antibody therapy was permitted. RESULTS: Objective response was observed in 50% of MM (7/14) and and 33% of HNSCC (2/6) patients. Belapectin+pembrolizumab was associated with fewer immune-mediated adverse events than anticipated with pembrolizumab monotherapy. There were no dose-limiting toxicities for belapectin within the dose range investigated. Significantly increased effector memory T-cell activation and reduced monocytic myeloid-derived suppressor cells (M-MDSCs) were observed in responders compared with non-responders. Increased baseline expression of Gal-3+ tumor cells and PD-1+CD8+ T cells in the periphery correlated with response as did higher serum trough levels of pembrolizumab. CONCLUSIONS: Belapectin+pembrolizumab therapy has activity in MM and HNSCC. Increased Gal-3 expression, expansion of effector memory T cells, and decreased M-MDSCs correlated with clinical response. Further investigation is planned.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas Sanguíneas/antagonistas & inibidores , Galectinas/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Pectinas/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteínas Sanguíneas/imunologia , Feminino , Galectinas/imunologia , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Células T de Memória/efeitos dos fármacos , Células T de Memória/imunologia , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/imunologia , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Pectinas/efeitos adversos , Receptor de Morte Celular Programada 1/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Fatores de Tempo , Resultado do TratamentoRESUMO
Treatment with programmed cell death 1 inhibitors is associated with a wide range of cutaneous immune-related adverse events, with lichenoid eruptions representing one of the major cutaneous toxicities. We describe the case of an 81-year-old man with metastatic melanoma treated with pembrolizumab who subsequently developed a delayed-onset generalized lichenoid dermatitis. After failing multiple lines of systemic immunosuppression, narrowband ultraviolet B (NBUVB) phototherapy three times per week for 17 sessions resulted in a significant clinical response in his cutaneous eruption and was well tolerated. NBUVB is a safe, lower-cost modality that induces local, skin-specific immunosuppression without the toxicities of traditional systemic immunosuppressive agents. To date, this is the first report of use of NBUVB in immune-related lichenoid dermatitis resistant to multiple standard therapies.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Inibidores de Checkpoint Imunológico/efeitos adversos , Erupções Liquenoides/radioterapia , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Terapia Ultravioleta , Idoso de 80 Anos ou mais , Humanos , Erupções Liquenoides/induzido quimicamente , Erupções Liquenoides/imunologia , Erupções Liquenoides/patologia , Masculino , Melanoma/imunologia , Melanoma/secundário , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
Programmed cell death protein1 (PD1)/programmed death protein ligand1 (PDL1) inhibitors for treatment of a various types of cancers have revolutionized cancer immunotherapy. However, PD1/PDL1 inhibitors are associated with a low response rate and are only effective on a small number of patients with cancer. Development of an antiPD1/PDL1 sensitizer for improving response rate and effectiveness of immunotherapy is a challenge. The present study reviews the synergistic effects of PD1/PDL1 inhibitor with oncolytic virus, tumor vaccine, molecular targeted drugs, immunotherapy, chemotherapy, radiotherapy, intestinal flora and traditional Chinese medicine, to provide information for development of effective combination therapies.
Assuntos
Antígeno B7-H1/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/terapia , Receptor de Morte Celular Programada 1/genética , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Imunoterapia/tendências , Neoplasias/genética , Neoplasias/imunologia , Terapia Viral Oncolítica/tendências , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologiaRESUMO
Although multiple immune checkpoint inhibitors (ICI) have been identified and tested in the clinic, antibodies blocking the PD-1/PD-L1 axis have produced the greatest impact on cancer treatment. Many potential mechanisms of treatment failure have been proposed from pre-clinical animal and human translational studies. Pre-clinical studies and clinical trials are underway to better understand how resistance arises and to develop strategies that can circumvent these resistance mechanisms and sensitize patients to anti-PD1/PD-L1 to improve clinical outcomes.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias/imunologiaRESUMO
Background: Anti-PD-1-based immunotherapy has emerged as a promising therapy for several cancers. However, it only benefits a small subset of colorectal cancer (CRC) patients. Mounting data supports the pivotal role of gut microbiota in shaping immune system. Pectin, a widely consumed soluble fiber, has been reported to ameliorate the imbalance of gut microbiota. Therefore, we aimed to explore the effect and the underlying mechanisms of pectin in improving anti-PD-1 mAb efficacy. Methods: The C57BL/6 mice were treated with a broad-spectrum antibiotic (ATB) cocktail to depleted endogenous gut microbiota and subsequently humanized with feces from healthy controls or newly diagnosed CRC patients. The antitumor efficacies of anti-PD-1 mAb combined with or without pectin were assessed using these mice. Flow cytometry and immunohistochemistry (IHC) were conducted to investigate the tumor immune microenvironment after treatment. The gut microbiota profiles and short-chain fatty acids (SCFAs) levels were determined by 16S ribosomal RNA (16S rRNA) gene sequencing and gas chromatography-mass spectrometry (GC-MS), respectively. The effect of gut microbiota on anti-PD-1 mAb efficacy after pectin supplement was further tested by fecal microbiota transplantation (FMT). Results: The anti-PD-1 mAb efficacy was largely impaired in the mice humanized with feces from newly diagnosed CRC patients compared to those from healthy controls. However, pectin significantly enhanced the anti-PD-1 mAb efficacy in the tumor-bearing mice humanized with CRC patient gut microbiota. Flow cytometry and IHC analysis revealed increased T cell infiltration and activation in the tumor microenvironment of mice treated with anti-PD-1 mAb plus pectin. In vivo depletion of CD8+ T cells diminished the anti-tumor effect of anti-PD-1 mAb combined with pectin. 16S rRNA gene sequencing showed that pectin significantly increased gut microbial diversity and beneficially regulated microbial composition. In addition, we identified unique bacterial modules that were significantly enriched in the anti-PD-1 mAb + pectin group, which composed of butyrate-producing bacteria indicative of good response to immunotherapy. Meanwhile, GC-MS showed that pectin altered the level of SCFA butyrate. Furthermore, butyrate, a main product of dietary fiber in gut microbial fermentation, was found to be sufficient to promote T cells infiltration and thus enhance the efficacy of anti-PD-1 mAb. In addition, FMT demonstrated the effects of pectin were dependent on gut microbiota. Importantly, the beneficial effects of pectin were confirmed in the mice humanized with gut microbiota from patient with resistance to anti-PD-1 mAb. Conclusion: Pectin facilitated the anti-PD-1 mAb efficacy in CRC via regulating the T cell infiltration in the tumor microenvironment, which was potentially mediated by the metabolite butyrate.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Microbioma Gastrointestinal/fisiologia , Pectinas/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Animais , Bactérias , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Ácidos Graxos Voláteis/metabolismo , Fezes/microbiologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S/metabolismo , Microambiente Tumoral/efeitos dos fármacosRESUMO
Therapeutic antibodies blocking PD-1-/PD-L1 interaction have achieved remarkable clinical success in cancer. In addition to blocking a target molecule, some isotypes of antibodies can activate complement, NK cells or phagocytes, resulting in death of the cell expressing the antibody's target. Human anti-PD-1 therapeutics use antibody isotypes designed to minimize such antibody-dependent lysis. In contrast, anti-PD-1 reagents used in mice are derived from multiple species, with different isotypes, and are not engineered to reduce target cell death: few studies analyze or discuss how antibody species and isotype may impact data interpretation. We demonstrate here that anti-PD-1 therapy to promote activation and proliferation of murine PD-1-expressing CD8 T cells sometimes led instead to a loss of antigen specific cells. This phenomenon was seen in two tumor models and a model of virus infection, and varied with the clone of anti-PD-1 antibody. Additionally, we compared competition among anti-PD-1 clones to find a combination that allows detection of PD-1-expressing cells despite the presence of blocking anti-PD1 antibodies in vivo. These data bring attention to the possibility of unintended target cell depletion with some commonly used anti-mouse PD-1 clones, and should provide a valuable resource for the design and interpretation of anti-PD-1 studies in mice.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por Herpesviridae/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Muromegalovirus/fisiologia , Sarcoma/imunologia , Neoplasias Cutâneas/imunologia , Animais , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/transplante , Morte Celular , Linhagem Celular Tumoral , Cricetinae , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Infecções por Herpesviridae/terapia , Humanos , Imunoglobulina G/metabolismo , Isotipos de Imunoglobulinas/metabolismo , Metilcolantreno , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ratos , Sarcoma/terapia , Neoplasias Cutâneas/terapiaRESUMO
BACKGROUND: Camrelizumab, which was launched in China on May 29, 2019, is a humanized anti-programmed cell death-1 (PD-1) antibody. It is used for the treatment of complicated or refractory classic Hodgkin's lymphoma with at least second-line chemotherapy. On March 4, 2020, camrelizumab was approved as a second-line drug in China for the treatment of advanced hepatocellular carcinoma. Currently, camrelizumab is undergoing clinical research for advanced solid tumors such as liver cancer, gastric cancer, esophageal cancer, and lung cancer, and all have shown clinical efficacy. OBJECTIVE: This review describes preclinical studies on camrelizumab and its efficacy and safety in clinical studies in various tumors. METHODS: A literature search was conducted on basic research and clinical trials of camrelizumab determined its pharmacology, toxicology, pharmacokinetic properties, and current clinical research status. We also analyzed the difference between camrelizumab and other PD-1 antibodies. RESULTS: The results of preclinical studies show that camrelizumab binds to the PD-1 receptor and has stable anti-tumor activity in a dose-dependent manner. Clinical studies show that camrelizumab has therapeutic effects on a variety of tumors. The incidence of adverse reactions with camrelizumab is low, with most being mild, reversible, and predictable. CONCLUSION: This review summarizes the current status of preclinical and clinical studies on camrelizumab. Current research confirms that camrelizumab alone or in combination with other drugs shows significant anti-cancer activity and a low incidence of adverse reactions. However, further studies are needed to verify the application potential of camrelizumab in a variety of tumors.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Neoplasias Esofágicas/tratamento farmacológico , Doença de Hodgkin/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológicoRESUMO
Idiosyncratic drug-induced liver injury (IDILI) is an idiosyncratic drug reaction that is specific to an individual and can lead to liver failure and even death. The mechanism of IDILI remains poorly understood, but most IDILI appears to be immune-mediated. We have developed the first validated animal model by using a PD-1-/- mouse model in combination with anti-CTLA-4 to block immune checkpoints and impair immune tolerance. Treatment of these mice with drugs that cause IDILI in humans led to delayed-onset liver injury with characteristics similar to IDILI in humans. The current study investigates the effects of green tea extract, a weight-loss dietary supplement that has been reported to cause IDILI in humans. Green tea extracts contain a highly variable content of catechins including (-)-epigallocatechin gallate, the major catechin in green tea formulations. If the liver injury caused by green tea extract in humans is immune-mediated, it may occur in our impaired immune tolerance model. Female PD-1-/- mice treated with anti-CTLA-4 antibody and green tea extract (500 mg/kg), a dose that is considered a no-observed-adverse-effect level for liver in rodents, produced a delayed onset increase in serum alanine transaminase levels and an increase in hepatic CD8+ T cells. In contrast, the response in male PD-1-/- mice was less pronounced, and there was no evidence of liver injury in wild-type mice. These findings are consistent with the hypothesis that the IDILI caused by green tea extract is immune-mediated and is similar to IDILI caused by medications that are associated with IDILI.
Assuntos
Catequina/farmacologia , Modelos Animais de Doenças , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Chá/química , Animais , Catequina/química , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Relação Dose-Resposta a Droga , Feminino , Tolerância Imunológica/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Extratos Vegetais/química , Receptor de Morte Celular Programada 1/deficiência , Receptor de Morte Celular Programada 1/imunologiaRESUMO
PURPOSE: Immunotherapy against immune checkpoints has significantly improved survival both in metastatic and adjuvant setting in several types of cancers. Thyroid dysfunction is the most common endocrine adverse event reported. Patients who are at risk of developing thyroid dysfunction remain to be defined. We aimed to identify predictive factors for the development of thyroid dysfunction during immunotherapy. METHODS: This is a retrospective study including a total of 68 patients who were treated with immune checkpoint inhibitors (ICIs) for metastatic or unresectable advanced cancers. The majority of patients were treated with anti-PD1 drugs in monotherapy or in combination with anti-CTLA4 inhibitors. Thyroid function and anti-thyroid antibodies, before starting immunotherapy and during treatment, were evaluated. Thyroid ultrasound was also performed in a subgroup of patients at the time of enrolment in the study. RESULTS: Eleven out of 68 patients (16.1%) developed immune-related overt thyroid dysfunction. By ROC curve analysis, we found that a serum TSH cut-off of 1.72 mUI/l, at baseline, had a good diagnostic accuracy in identifying patients without overt thyroid dysfunction (NPV = 100%, p = 0.0029). At multivariate analysis, both TSH and positive anti-thyroid antibodies (ATAbs) levels, before ICIs treatment, were independently associated with the development of overt thyroid dysfunction during immunotherapy (p = 0.0001 and p = 0.009, respectively). CONCLUSIONS: Pre-treatment serum TSH and ATAbs levels may help to identify patients at high risk for primary thyroid dysfunction. Our study suggests guidance for an appropriate timely screening and for a tailored management of thyroid dysfunctions in patients treated with ICIs.
Assuntos
Inibidores de Checkpoint Imunológico , Imunoterapia/efeitos adversos , Neoplasias , Doenças da Glândula Tireoide , Autoanticorpos/sangue , Antígeno CTLA-4/antagonistas & inibidores , Feminino , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/métodos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/patologia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos Retrospectivos , Medição de Risco/métodos , Doenças da Glândula Tireoide/diagnóstico , Doenças da Glândula Tireoide/etiologia , Doenças da Glândula Tireoide/imunologia , Testes de Função Tireóidea/métodos , Testes de Função Tireóidea/estatística & dados numéricos , Tireotropina/sangueRESUMO
A series of novel linear aliphatic amine-linked triaryl derivatives as inhibitors of PD-1/PD-L1 were designed, synthesized, and evaluated in vitro and in vivo. In this chemical series, compound 58 showed the most potent inhibitory activity and binding affinity with hPD-L1, with an IC50 value of 12 nM and a KD value of 16.2 pM, showing a binding potency approximately 2000-fold that of hPD-1. Compound 58 could bind with hPD-L1 on the cellular surface and competitively block the interaction of hPD-1 with hPD-L1. In a T cell function assay, 58 restored the T cell function, leading to increased IFN-γ secretion. Moreover, in a humanized mouse model, compound 58 significantly inhibited tumor growth without obvious toxicity and showed moderate PK properties after intravenous injection. These results indicated that 58 is a promising lead for further development of small-molecule PD-1/PD-L1 inhibitors for cancer therapy.