scholarly journals Complete remission in a patient with widely metastatic HER2-amplified pancreatic adenocarcinoma following multimodal therapy informed by tumor sequencing and organoid profiling

2021 ◽  
Author(s):  
Daniel A King ◽  
Amber R Smith ◽  
Gino Pineda ◽  
Michitaka Nakano ◽  
Flavia Michelini ◽  
...  
Keyword(s):  
Complete Remission ◽  
Pancreatic Adenocarcinoma ◽  
Drug Testing ◽  
Drug Sensitivity ◽  
Multimodal Therapy ◽  
T Cell Response ◽  
Ductal Adenocarcinoma ◽  
Response Monitoring ◽  
Checkpoint Inhibition ◽  
Tumor Sequencing

This work, "Complete remission in a patient with widely metastatic HER2-amplified pancreatic adenocarcinoma following multimodal therapy informed by tumor sequencing and organoid profiling" highlights the power of multi-institution collaboration, combining strengths in organoid profiling (Kuo group at Stanford), personalized vaccine therapy (Gillanders group at WUSTL), in vitro drug testing and drug sensitivity (SEngine, MSK, and Mprobe), clinical trials (Dr Ari Baron at CPMC), and the Canopy Health learning network. Here, we demonstrate a complete clinical response achieved in a patient with HER2+ metastatic pancreatic ductal adenocarcinoma to a coordinated barrage of anti-HER2, personalized vaccine and checkpoint inhibition immunotherapy, radiation, and chemotherapy. Comprehensive organoid profiling with drug sensitivity screening and drug testing suggested a vulnerability to anti-HER2 directed therapy, facilitating personalized treatment selection for our patient, which contributed to her clinical benefit. Immune response monitoring following personalized vaccine, radiation and checkpoint inhibition showed a sustained increase in neoantigen specific T cell response.

Management of Pancreatic Adenocarcinoma

2017 ◽  
Author(s):  
Alexandra G Lopez-Aguiar ◽  
Shishir K Maithel ◽  
David A Kooby
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Multimodal Therapy ◽  
Locally Advanced ◽  
Ductal Adenocarcinoma ◽  
R0 Resection ◽  
Poor Overall Survival ◽  
Borderline Resectable ◽  
Resectable Disease ◽  
Unresectable Disease ◽  
Common Operation

Pancreatic ductal adenocarcinoma is a lethal disease with a poor overall survival. Surgery remains the only potential curative option, and multimodal therapy is typically indicated. Pancreatic cancer can be categorized into four groups according to presentation: resectable disease, borderline resectable disease, locally advanced unresectable disease, and metastatic unresectable disease. Pancreaticoduodenectomy is the most common operation performed for patients with resectable and borderline resectable disease, followed by distal pancreatectomy, and, rarely, total pancreatectomy, with the goal of obtaining an R0 resection. The morbidity associated with these procedures remains high, and thoughtful patient selection is paramount. Postoperative chemotherapy protocols, with or without radiotherapy, are standard, and neoadjuvant therapy is gaining momentum. This review summarizes appropriate management of resectable pancreatic adenocarcinoma. This review contains 12 figures, 5 tables and 49 references

Management of Pancreatic Adenocarcinoma

2017 ◽  
Author(s):  
Alexandra G Lopez-Aguiar ◽  
Shishir K Maithel ◽  
David A Kooby
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Multimodal Therapy ◽  
Locally Advanced ◽  
Ductal Adenocarcinoma ◽  
R0 Resection ◽  
Poor Overall Survival ◽  
Borderline Resectable ◽  
Resectable Disease ◽  
Unresectable Disease ◽  
Common Operation

Pancreatic ductal adenocarcinoma is a lethal disease with a poor overall survival. Surgery remains the only potential curative option, and multimodal therapy is typically indicated. Pancreatic cancer can be categorized into four groups according to presentation: resectable disease, borderline resectable disease, locally advanced unresectable disease, and metastatic unresectable disease. Pancreaticoduodenectomy is the most common operation performed for patients with resectable and borderline resectable disease, followed by distal pancreatectomy, and, rarely, total pancreatectomy, with the goal of obtaining an R0 resection. The morbidity associated with these procedures remains high, and thoughtful patient selection is paramount. Postoperative chemotherapy protocols, with or without radiotherapy, are standard, and neoadjuvant therapy is gaining momentum. This review summarizes appropriate management of resectable pancreatic adenocarcinoma. This review contains 12 figures, 5 tables and 49 references

scholarly journals Modulation of temozolomide dose differentially affects T-cell response to immune checkpoint inhibition

2019 ◽  
Vol 21 (6) ◽  
pp. 730-741 ◽  
Author(s):  
Aida Karachi ◽  
Changlin Yang ◽  
Farhad Dastmalchi ◽  
Elias J Sayour ◽  
Jianping Huang ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Standard Dose ◽  
Antibody Therapy ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Response ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Dose Modulation ◽  
Infiltrating Lymphocytes

Abstract Background The changes induced in host immunity and the tumor microenvironment by chemotherapy have been shown to impact immunotherapy response in both a positive and a negative fashion. Temozolomide is the most common chemotherapy used to treat glioblastoma (GBM) and has been shown to have variable effects on immune response to immunotherapy. Therefore, we aimed to determine the immune modulatory effects of temozolomide that would impact response to immune checkpoint inhibition in the treatment of experimental GBM. Methods Immune function and antitumor efficacy of immune checkpoint inhibition were tested after treatment with metronomic dose (MD) temozolomide (25 mg/kg × 10 days) or standard dose (SD) temozolomide (50 mg/kg × 5 days) in the GL261 and KR158 murine glioma models. Results SD temozolomide treatment resulted in an upregulation of markers of T-cell exhaustion such as LAG-3 and TIM-3 in lymphocytes which was not seen with MD temozolomide. When temozolomide treatment was combined with programmed cell death 1 (PD-1) antibody therapy, the MD temozolomide/PD-1 antibody group demonstrated a decrease in exhaustion markers in tumor infiltrating lymphocytes that was not observed in the SD temozolomide/PD-1 antibody group. Also, the survival advantage of PD-1 antibody therapy in a murine syngeneic intracranial glioma model was abrogated by adding SD temozolomide to treatment. However, when MD temozolomide was added to PD-1 inhibition, it preserved the survival benefit that was seen by PD-1 antibody therapy alone. Conclusion The peripheral and intratumoral immune microenvironments are distinctively affected by dose modulation of temozolomide.

Adjuvant and Neoadjuvant Therapy for Pancreatic Adenocarcinoma

2017 ◽  
Author(s):  
Gregory C Wilson ◽  
Brent T Xia ◽  
Syed A Ahmed
Keyword(s):  
Pancreatic Cancer ◽  
Adjuvant Therapy ◽  
Neoadjuvant Therapy ◽  
Pancreatic Adenocarcinoma ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Advanced Pancreatic Cancer ◽  
Treatment Strategies ◽  
Ductal Adenocarcinoma ◽  
Borderline Resectable

Despite decades of advancement and research into the multimodal care of pancreatic cancer, mortality after the diagnosis of pancreatic ductal adenocarcinoma remains grim. The role of adjuvant therapy following surgical resection has been well established in the literature. However, adjuvant therapy is imperfect, and outside of a clinical trial, there are high rates of omission or delayed initiation of therapy. Neoadjuvant treatment strategies continue to be explored in the management of resectable, borderline-resectable, and locally advanced unresectable pancreatic adenocarcinoma. With improved resection rates and the possibility for tumor downstaging, neoadjuvant therapy has become standard for patients with borderline-resectable and locally advanced unresectable tumors. Additional benefits of neoadjuvant therapy in the treatment of resectable tumors include improved completion rates of systemic therapy and R0 resection rates. Future clinical trials, including the use of novel treatment agents and combination treatment strategies in both neoadjuvant and adjuvant regimens, will add value to the treatment of pancreatic adenocarcinoma. Key words: adjuvant therapy, borderline-resectable pancreatic cancer, locally advanced pancreatic cancer, neoadjuvant therapy, pancreatic adenocarcinoma, resectable disease 

scholarly journals Application of an ex-vivo drug sensitivity platform towards achieving complete remission in a refractory T-cell lymphoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sanjay de Mel ◽  
Masturah B. M. Rashid ◽  
Xi Yun Zhang ◽  
Jasmine Goh ◽  
Chun Tsu Lee ◽  
...  
Keyword(s):  
T Cell ◽  
Complete Remission ◽  
Drug Sensitivity ◽  
Cell Lymphoma ◽  
Ex Vivo ◽  
T Cell Lymphoma

scholarly journals Pancreatic cancer-derived organoids – a disease modeling tool to predict drug response

2020 ◽  
Vol 8 (5) ◽  
pp. 594-606 ◽  
Author(s):  
Pierre-Olivier Frappart ◽  
Karolin Walter ◽  
Johann Gout ◽  
Alica K Beutel ◽  
Mareen Morawe ◽  
...  
Keyword(s):  
Drug Testing ◽  
Disease Modeling ◽  
Individualized Medicine ◽  
Expression Patterns ◽  
Culture Conditions ◽  
Ductal Adenocarcinoma ◽  
Small Scale ◽  
Comparative Genomic

Background Organotypic cultures derived from pancreatic ductal adenocarcinoma (PDAC) termed pancreatic ductal cancer organoids (PDOs) recapitulate the primary cancer and can be derived from primary or metastatic biopsies. Although isolation and culture of patient-derived pancreatic organoids were established several years ago, pros and cons for individualized medicine have not been comprehensively investigated to date. Methods We conducted a feasibility study, systematically comparing head-to-head patient-derived xenograft tumor (PDX) and PDX-derived organoids by rigorous immunohistochemical and molecular characterization. Subsequently, a drug testing platform was set up and validated in vivo. Patient-derived organoids were investigated as well. Results First, PDOs faithfully recapitulated the morphology and marker protein expression patterns of the PDXs. Second, quantitative proteomes from the PDX as well as from corresponding organoid cultures showed high concordance. Third, genomic alterations, as assessed by array-based comparative genomic hybridization, revealed similar results in both groups. Fourth, we established a small-scale pharmacotyping platform adjusted to operate in parallel considering potential obstacles such as culture conditions, timing, drug dosing, and interpretation of the results. In vitro predictions were successfully validated in an in vivo xenograft trial. Translational proof-of-concept is exemplified in a patient with PDAC receiving palliative chemotherapy. Conclusion Small-scale drug screening in organoids appears to be a feasible, robust and easy-to-handle disease modeling method to allow response predictions in parallel to daily clinical routine. Therefore, our fast and cost-efficient assay is a reasonable approach in a predictive clinical setting.

Oral and Pharyngeal Cancer: Combined Approach for Multimodal Therapy

1983 ◽  
Vol 69 (6) ◽  
pp. 563-566 ◽  
Author(s):  
Massimo Fazio ◽  
Fausto Badellino ◽  
Gian Luca Sannazzari ◽  
Vittorio Vercellino ◽  
Mario Airoldi ◽  
...  
Keyword(s):  
Lymph Node ◽  
Complete Remission ◽  
Cancer Patients ◽  
Multimodal Therapy ◽  
Combined Approach ◽  
Pharyngeal Cancer ◽  
Chi Square ◽  
Actuarial Survival ◽  
Oral And Pharyngeal Cancer ◽  
Chi Square Test

Five-year results in 60 oral and pharyngeal cancer patients treated with combined apporach chemoradiotherapy (39 patients) and chemoradiotherapy plus lymph node surgery (21 patients) are reported. Complete remission (CR) was achieved in 16/39 (41%) patients treated with chemoradiotherapy alone, and in 16/21 (76%) patients who had chemoradiotherapy plus surgery. The number of CR was statistically (chi-square test) higher (p < 0.025) in the second group. The 5-year actuarial survival was 39.7% in the group of patients treated with chemoradiotherapy plus surgery. After 5 years 53% of the patients who reached CR are living free of disease in the first group and 76% in the second group.

scholarly journals RARE-26. WHOLE GENOME SEQUENCING OF AN OSSEOUS METASTASIS DURING CHECKPOINT-CONTROLLED INTRACRANIAL GLIOBLASTOMA REVEALS NEW INSIGHTS INTO POTENTIAL MECHANISMS OF IMMUNE ESCAPE

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi227-vi227
Author(s):  
Malte Mohme ◽  
Cecile Maire ◽  
Simon Schliffke ◽  
Simon Joosse ◽  
Malik Alawi ◽  
...  
Keyword(s):  
T Cell ◽  
Bone Metastasis ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cell Response ◽  
Immune Escape ◽  
T Cell Response ◽  
Molecular Profile ◽  
Whole Genome ◽  
Checkpoint Inhibition

Abstract Glioblastoma (GBM) has a devastating prognosis and recent advances in the treatment of a variety of cancer entities, e.g. through checkpoint inhibition, could so far not be translated into improved outcome in newly-diagnosed GBM. Characterizing rare cases of peripheral metastases which succeeded in overcoming immune control, can help to understand the mechanisms of immune escape. Here we describe the first reported case of a detailed genetic and immunological characterization of a peripheral bone metastasis from a GBM which was controlled intracranially by anti-PD1 checkpoint inhibition We performed whole genome sequencing (WGS) of the primary- and recurrent tumor, as well as the bone metastasis. Genomic data was analyzed for copy number variations and mutational profiles. In addition, immune monitoring with flow cytometric phenotyping and next-generation sequencing of the peripheral T-cell repertoire was used. A 70-year old patient developed multiple osseous metastases in the spine, while his IDHwt GBM recurrence was immunologically controlled with checkpoint inhibition. Biopsy confirmed peripheral GBM metastases. Immunophenotyping reflected the effective activation of the peripheral T-cell response, with, however, simultaneous upregulation of regulatory T-cells during disease progression. WGS sequencing demonstrated a distinct molecular profile of the GBM metastasis, with amplifications in chromosome 3 and 9, as well as genomic loss on chromosomes 4, 10 and 11. The peripheral metastasis was distinguished by mutations in mismatch repair genes, such as MSH4 and MLH1, associated with a hypermutated phenotype. Among the mutated genes we found potential candidates involved in immune escape of circulating tumor cells. This case represents a unique opportunity to analyze potential mechanisms of GBM-mediated immune escape during immune activation with anti-PD1 checkpoint therapy. It highlights the fact, that although an effective, disinhibited immune response can control the cranial GBM disease, hypermutated tumor clones can evade the tumor-specific T-cell response and disseminate to distant organs.

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