scholarly journals Combination therapy for mCRPC with immune checkpoint inhibitors, ADT and vaccine: A mathematical model

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262453
Author(s):  
Nourridine Siewe ◽  
Avner Friedman
Keyword(s):  
Mathematical Model ◽  
Clinical Trials ◽  
Tumor Volume ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Fold Increase ◽  
Castration Resistant Prostate Cancer ◽  
Negative Effects ◽  
Initial Tumor ◽  
Density Concentration

Metastatic castration resistant prostate cancer (mCRPC) is commonly treated by androgen deprivation therapy (ADT) in combination with chemotherapy. Immune therapy by checkpoint inhibitors, has become a powerful new tool in the treatment of melanoma and lung cancer, and it is currently being used in clinical trials in other cancers, including mCRPC. However, so far, clinical trials with PD-1 and CTLA-4 inhibitors have been disappointing. In the present paper we develop a mathematical model to assess the efficacy of any combination of ADT with cancer vaccine, PD-1 inhibitor, and CTLA-4 inhibitor. The model is represented by a system of partial differential equations (PDEs) for cells, cytokines and drugs whose density/concentration evolves in time within the tumor. Efficacy of treatment is determined by the reduction in tumor volume at the endpoint of treatment. In mice experiments with ADT and various combinations of PD-1 and CTLA-4 inhibitors, tumor volume at day 30 was always larger than the initial tumor. Our model, however, shows that we can decrease tumor volume with large enough dose; for example, with 10 fold increase in the dose of anti-PD-1, initial tumor volume will decrease by 60%. Although the treatment with ADT in combination with PD-1 inhibitor or CTLA-4 inhibitor has been disappointing in clinical trials, our simulations suggest that, disregarding negative effects, combinations of ADT with checkpoint inhibitors can be effective in reducing tumor volume if larger doses are used. This points to the need for determining the optimal combination and amounts of dose for individual patients.

scholarly journals Immune Deregulation in Sepsis and Septic Shock: Reversing Immune Paralysis by Targeting PD-1/PD-L1 Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuki Nakamori ◽  
Eun Jeong Park ◽  
Motomu Shimaoka
Keyword(s):  
Clinical Trials ◽  
T Lymphocytes ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Specific Treatment ◽  
Multiple Organ ◽  
Lymphoid Cells ◽  
Immune Checkpoints ◽  
Drug Candidates ◽  
Immune Paralysis

Sepsis remains a major problem for human health worldwide, thereby manifesting high rates of morbidity and mortality. Sepsis, once understood as a monophasic sustained hyperinflammation, is currently recognized as a dysregulated host response to infection, with both hyperinflammation and immunoparalysis occurring simultaneously from the earliest stages of sepsis, involving multiple organ dysfunctions. Despite the recent progress in the understanding of the pathophysiology underlying sepsis, no specific treatment to restore immune dysregulation in sepsis has been validated in clinical trials. In recent years, treatment for immune checkpoints such as the programmed cell death protein 1/programmed death ligand (PD-1/PD-L) pathway in tumor-infiltrating T-lymphocytes has been successful in the field of cancer immune therapy. As immune-paralysis in sepsis involves exhausted T-lymphocytes, future clinical applications of checkpoint inhibitors for sepsis are expected. In addition, the functions of PD-1/PD-L on innate lymphoid cells and the role of exosomal forms of PD-L1 warrant further research. Looking back on the history of repeatedly failed clinical trials of immune modulatory therapies for sepsis, sepsis must be recognized as a difficult disease entity for performing clinical trials. A major obstacle that could prevent effective clinical trials of drug candidates is the disease complexity and heterogeneities; clinically diagnosed sepsis could contain multiple sepsis subgroups that suffer different levels of hyper-inflammation and immune-suppression in distinct organs. Thus, the selection of appropriate more homogenous sepsis subgroup is the key for testing the clinical efficacy of experimental therapies targeting specific pathways in either hyperinflammation and/or immunoparalysis. An emerging technology such as artificial intelligence (AI) may help to identify an immune paralysis subgroup who would best be treated by PD-1/PD-L1 pathway inhibitors.

Prospective trial of nivolumab (Nivo) plus radium-223 (RA) in metastatic castration-resistant prostate cancer (mCRPC) evaluating circulating tumor DNA (ctDNA) levels as a biomarker of response.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS267-TPS267
Author(s):  
Benjamin Louis Maughan ◽  
Roberto Nussenzveig ◽  
Umang Swami ◽  
Sumati Gupta ◽  
Neeraj Agarwal
Keyword(s):  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Prospective Trial ◽  
Progression Free Survival ◽  
Metastatic Gastric Cancer ◽  
Circulating Tumor Dna ◽  
Alpha Particles ◽  
Response To Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Radium 223

TPS267 Background: RA is a calcium-mimetic radiopharmaceutical emitter of alpha particles that has been approved for treatment of mCRPC. Radiation plus checkpoint inhibitors has demonstrated promising efficacy in previous clinical trials (PMID 27466265, 23535954). Alteration to PD-1 expression has been observed with radium-223, suggesting potential synergy with Nivo (PMID 29137877). ctDNA concentration may accurately reflect overall tumor burden and response to immune therapy. ctDNA testing after 6 weeks of therapy predicts efficacy of immunotherapy in patients with metastatic NSCLC and urothelial carcinoma (PMID 30093454) and metastatic gastric cancer (PMID 30013197). Reduction of ctDNA correlated with both radiographic progression free survival (rPFS) and overall survival. We hypothesize that RA + Nivo will be safe and decrease ctDNA, which may predict response to therapy earlier than conventional scans. Methods: This is a single-arm phase I/II investigator initiated trial (NCT04109729). Primary objectives: 1) Safety, 2) Change in ctDNA after 6 weeks treatment compared to baseline. Secondary objectives: 1) PSA-PFS; 2) PSA 50% response rate; 3) Time to skeletal related event; 4) Bone metabolism marker response. Inclusion criteria: symptomatic bone metastasis, mCRPC, adequate hematopoiesis. Exclusion criteria: visceral metastasis, history of autoimmune disease and current use of immune suppression therapy. A total of 36 patients will be enrolled. Cycles are 28 days. ctDNA concentration will be measured using GuardantOMNI research platform which evaluates 500 genes. Treatment: RA (55 kBq/kg IV) monotherapy lead in for two cycles followed by RA plus Nivo (480mg IV) for an additional 4 cycles. Nivo monotherapy then continues for up to 2 years. ctDNA collected prior to combination therapy and 6 weeks after. Restaging scans done every 2 cycles while on radium-223 and every 3 cycles while on nivolumab. Clinical trial information: NCT04109729.

Investigating racial differences in treatment responses through analysis of real-world data (RWD).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18141-e18141
Author(s):  
Zongzhi Liu ◽  
Meng Ma ◽  
Kartikey Grover ◽  
Li Li ◽  
Howard Goldsweig ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Racial Differences ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Metastatic Breast ◽  
Therapeutic Agents ◽  
Rank Test ◽  
Castration Resistant Prostate Cancer ◽  
Real World Data ◽  
Clinical Records

e18141 Background: Clinical trials remain the most reliable means to evaluate drug efficacy and safety for evidence-based cancer care. However, there is a significant racial disparity among participants in clinical trials. For example, only 1-3% of the participants in registration trials of immune checkpoint inhibitors (CPIs) in advanced non-small cell lung cancers (aNSCLCs) were Black. RWD data enable assessment of whether clinical trial results can be generalized to broader populations. Methods: We analyzed clinical records of > 145,000 cancer patients treated at Mount Sinai hospitals. Therapeutic agents approved by FDA in recent years were assessed for responses across various race groups. Time to treatment discontinuation (TTD) was used as a surrogate clinical endpoint for outcomes. Results: Overall we did not observe significant differences in TTD among different race groups for the following drugs and indications we examined: palbociclib in metastatic breast cancer (mBC), EGFR tyrosine kinase inhibitors in aNSCLC, EGFR antibody cetuximab and panitumumab in metastatic colorectal cancer with wild type KRAS, abiraterone in metastatic castration-resistant prostate cancer (mCRPC), enzalutamide in mCRPC, sorafenib in unresectable hepatocellular carcinoma (HCC), CPIs in metastatic melanoma. For example, the median TTD of palbociclib in combination with fulvestrant or letrozole in post-menopausal women with HR+HER2- mBC was 181, 261, and 160 days in White (n = 114), Black (n = 55), other (n = 48) race groups, respectively (P = 0.61, log-rank test). Among patients with unresectable HCC treated with sorafenib, the median TTD was 64, 49, and 67 days in the White (n = 201), Black (n = 127) and other (n = 243) race groups, respectively (P = 0.70). However, when CPIs in aNSCLC were examined, we observed a significantly longer TTD in the Black group (median TTD not reached; n = 77) compare to the non-Black group (169 days, 95% CI 133-331; n = 211), P = 0.0049, median follow up 194 days. Conclusions: RWD showed there are no apparent differences of treatment response in various race groups for most new therapeutic agents. Preliminary results of CPIs in aNSCLC suggested a favorable response in the Black than the non-Black population.

scholarly journals PROSPECTS OF COMBINING INTERLEUKIN-2 WITH IMMUNE CHECKPOINT INHIBITORS FOR CANCER THERAPY

2020 ◽  
Vol 66 (1) ◽  
pp. 23-28
Author(s):  
Mikhail Kiselevskiy ◽  
Irina Chikileva ◽  
O. Zharkova ◽  
N. Ziganshina ◽  
Lyubov Korolenkova ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Interleukin 2 ◽  
Combination Therapies ◽  
Activated Lymphocytes ◽  
Therapy Strategy ◽  
Clinical Investigations

The review summarizes results of pre-clinical and clinical investigations of combination therapies with interleukin-2 and immune checkpoint inhibitors. It presents data of the current registered clinical trials of immune checkpoint combinations either with interleukin-2 or the cytokine-activated lymphocytes. The up-to-date experimental and preliminary clinical data evidence that such an immune therapy strategy is highly promising for cancer treatment.

Modelling and Simulation of NO2 Dispersion Phenomenon in Atmosphere by Analytical-Experimental Methods

2008 ◽  
Vol 59 (10) ◽  
Author(s):  
Delia Perju ◽  
Harieta Pirlea ◽  
Gabriela-Alina Brusturean ◽  
Dana Silaghi-Perju ◽  
Sorin Marinescu
Keyword(s):  
Mathematical Model ◽  
Nitrogen Dioxide ◽  
Modeling And Simulation ◽  
Human Health ◽  
Experimental Methods ◽  
Negative Effects ◽  
Real Situation ◽  
Experimental Values ◽  
The Mathematical Model

The European laws and recently the Romanian ones impose more and more strict norms to the large nitrogen dioxide polluters. They are obligated to continuously improve the installations and products so that they limit and reduce the nitrogen dioxide pollution, because it has negative effects on the human health and environment. In this paper are presented these researches made within a case study for the Timi�oara municipality, regarding the modeling and simulation of the nitrogen dioxide dispersion phenomenon coming from various sources in atmosphere with the help of analytical-experimental methods. The mathematical model resulting from these researches is accurately enough to describe the real situation. This was confirmed by comparing the results obtained based on the model with real experimental values.

scholarly journals Novel immune checkpoints beyond PD-1 in advanced melanoma

2021 ◽  
Author(s):  
Nina Zila ◽  
Christoph Hoeller ◽  
Verena Paulitschke
Keyword(s):  
Clinical Trials ◽  
Checkpoint Inhibitors ◽  
Short Review ◽  
Therapy Resistance ◽  
Advanced Melanoma ◽  
Immune Checkpoints ◽  
Malignant Diseases ◽  
Foreseeable Future ◽  
Cell Responses ◽  
Therapeutic Landscape

SummaryIn malignant diseases, targeting of immune checkpoints successfully changed the therapeutic landscape and helped to unleash anti-tumor T cell responses, resulting in durable clinical outcomes, but only in up to 50% of patients. The success of these therapies and the need to overcome intrinsic and acquired therapy resistance stimulated research to identify new pathways and targets. Numerous clinical trials are currently evaluating novel checkpoint inhibitors or recently developed strategies like modulating the tumor microenvironment, mostly in combination with approved therapies. This short review briefly discusses promising therapeutic targets, currently still under investigation, with the chance to realize clinical application in the foreseeable future.

scholarly journals Comparison of pretherapeutic osseous tumor volume and standard hematology for prediction of hematotoxicity after PSMA-targeted radioligand therapy

2021 ◽  
Author(s):  
Liam Widjaja ◽  
Rudolf A. Werner ◽  
Tobias L. Ross ◽  
Frank M. Bengel ◽  
Thorsten Derlin
Keyword(s):  
Multivariate Analysis ◽  
Tumor Volume ◽  
Predictive Performance ◽  
Castration Resistant Prostate Cancer ◽  
Operating Characteristics ◽  
Predictive Capability ◽  
Radioligand Therapy ◽  
Castration Resistant ◽  
Pet Ct ◽  
Late Stages

Abstract Purpose Hematotoxicity is a potentially dose-limiting adverse event in patients with metastasized castration-resistant prostate cancer (mCRPC) undergoing prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT). We aimed to identify clinical or PSMA-targeted imaging-derived parameters to predict hematological adverse events at early and late stages in the treatment course. Methods In 67 patients with mCRPC scheduled for 177Lu-PSMA-617 RLT, pretherapeutic osseous tumor volume (TV) from 68Ga-PSMA-11 PET/CT and laboratory values were assessed. We then tested the predictive capability of these parameters for early and late hematotoxicity (according to CTCAE vers. 5.0) after one cycle of RLT and in a subgroup of 32/67 (47.8%) patients after four cycles of RLT. Results After one cycle, 10/67 (14.9%) patients developed leukocytopenia (lymphocytopenia, 39/67 [58.2%]; thrombocytopenia, 17/67 [25.4%]). A cut-off of 5.6 × 103/mm3 for baseline leukocytes was defined by receiver operating characteristics (ROC) and separated between patients with and without leukocytopenia (P < 0.001). Baseline leukocyte count emerged as a stronger predictive factor in multivariate analysis (hazard ratio [HR], 33.94, P = 0.001) relative to osseous TV (HR, 14.24, P = 0.01). After four cycles, 4/32 (12.5%) developed leukocytopenia and the pretherapeutic leukocyte cut-off (HR, 9.97, P = 0.082) tended to predict leukocytopenia better than TV (HR, 8.37, P = 0.109). In addition, a cut-off of 1.33 × 103/mm3 for baseline lymphocytes separated between patients with and without lymphocytopenia (P < 0.001), which was corroborated in multivariate analysis (HR, 21.39, P < 0.001 vs. TV, HR, 4.57, P = 0.03). After four cycles, 19/32 (59.4%) developed lymphocytopenia and the pretherapeutic cut-off for lymphocytes (HR, 46.76, P = 0.007) also demonstrated superior predictive performance for late lymphocytopenia (TV, HR, 5.15, P = 0.167). Moreover, a cut-off of 206 × 103/mm3 for baseline platelets separated between patients with and without thrombocytopenia (P < 0.001) and also demonstrated superior predictive capability in multivariate analysis (HR, 115.02, P < 0.001 vs.TV, HR, 12.75, P = 0.025). After four cycles, 9/32 (28.1%) developed thrombocytopenia and the pretherapeutic cut-off for platelets (HR, 5.44, P = 0.048) was also superior for the occurrence of late thrombocytopenia (TV, HR, 1.44, P = 0.7). Conclusions Pretherapeutic leukocyte, lymphocyte, and platelet levels themselves are strong predictors for early and late hematotoxicity under PSMA-directed RLT, and are better suited than PET-based osseous TV for this purpose.

scholarly journals RARE-55. CHALLENGES AND SPECIFIC STRATEGIES FOR CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY SYNDROME IN LOW RESOURCE SETTINGS. ON BEHALF OF THE INTERNATIONAL RRD CONSORTIUM IN LOW RESOURCE SETTINGS PANEL

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii454-iii454
Author(s):  
Rejin Kebudi ◽  
Nisreen Amayiri N ◽  
Malak Abedalthagafi ◽  
Asim Noor Rana ◽  
Slman Kirmani ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Malignant Gliomas ◽  
Mismatch Repair Deficiency ◽  
Term Survival ◽  
Low Resource Settings ◽  
Low Resource ◽  
Repair Deficiency ◽  
Constitutional Mismatch Repair Deficiency

Abstract Germline biallelic mutations in one of the mismatch repair genes (MSH2/MSH6/MLH1/PMS2 results in constitutional mismatch repair deficiency (CMMRD), a condition associated with multiple tumors arising from multiple organs during childhood, and these individuals rarely reach adulthood. The paucity of information with respect to these conditions leads to mismanagement and may be a factor in the high mortality of patients with CMMRD. Two international consortia, the European CARE4CMMRD, and the international replication repair deficiency (RRD) consortium, are addressing the many challenges associated with this condition. To address specific issues surrounding the management of CMMRD in low and middle income countries (LMIC), a multidisciplinary taskforce of 11 specialists from nine countries was formed. Preliminary conclusions are: 1) Immunohistochemistry for CMMRD should be considered for all patients with suggestive clinical features. In countries where CMMRD is common, malignant gliomas, colon cancers and T cell lymphomas should be stained routinely as the prevalence of CMMRD in these tumors can exceed 40%. 2) Temozolomide should not be used in the management of malignant glioma. By contrast, preclinical studies have suggested increased sensitivity to nitrosoureas. For the management of CMMRD related lymphoma and leukemia, mercaptopurines should not be avoided or discontinued as a part of the standard of care before more data are collected. 3) Management with checkpoint inhibitors should be limited to centers with intensive care units and expertise in complex supportive care to manage side effects of immune therapy. 4) Surveillance protocols have demonstrated long term survival benefits and should be implemented in LMIC.

scholarly journals Effectiveness and Safety of Immune Checkpoint Inhibitors for Patients with Advanced Non Small-Cell Lung Cancer in Real-World: Review and Meta-Analysis

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1388
Author(s):  
Manlio Mencoboni ◽  
Marcello Ceppi ◽  
Marco Bruzzone ◽  
Paola Taveggia ◽  
Alessia Cavo ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Real World ◽  
Group Performance ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Small Cell ◽  
Small Cell Lung ◽  
Eligibility Criteria

Immunotherapy based on anti PD-1/PD-L1 inhibitors is the new standard of advanced non-small cell lung cancers. Pembrolizumab, nivolumab and atezolizumab are used in clinical practice. The strict eligibility criteria of clinical trials do not allow researchers to fully represent treatment effects in the patients that will ultimately use these drugs. We performed a systematic review and a meta-analysis to evaluate the effectiveness and safety of these drugs, and more generally of ICIs, as second-line therapy in NSCLC patients in real world practice. MEDLINE, PubMed, Scopus and Web of Science were searched to include original studies published between January 2015 and April 2020. A total of 32 studies was included in the meta-analysis. The overall radiological response rate (ORR), disease control rate (DCR), median progression-free survival (PFS) and overall survival (OS) were 21%, 52%, 3.35 months and 9.98 months, respectively. The results did not change when analysis was adjusted for Eastern Cooperative Oncology Group performance status (ECOG PS) and age. A unitary increase in the percent of patients with liver and CNS metastases reduced the occurrence of DCR by 7% (p < 0.001) and the median PFS by 2% (p = 0.010), respectively. The meta-analysis showed that the efficacy and safety of immunotherapy in everyday practice is comparable to that in clinical trials.

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