Publications by authors named "Thomas T DeLeon"

9 Publications

  • Page 1 of 1

Assessment of clinical outcomes with immune checkpoint inhibitor therapy in melanoma patients with CDKN2A and TP53 pathogenic mutations.

PLoS One 2020 20;15(3):e0230306. Epub 2020 Mar 20.

Department of Hematology & Oncology, Mayo Clinic Arizona, Scottsdale, Arizona, United States of America.

Background: CDKN2A and TP53 mutations are recurrent events in melanoma, occurring in 13.3% and 15.1% of cases respectively and are associated with poorer outcomes. It is unclear what effect CDKN2A and TP53 mutations have on the clinical outcomes of patients treated with checkpoint inhibitors.

Methods: All patients with cutaneous melanoma or melanoma of unknown primary who received checkpoint inhibitor therapy and underwent genomic profiling with the 50-gene Mayo Clinic solid tumor targeted cancer gene panel were included. Patients were stratified according to the presence or absence of mutations in BRAF, NRAS, CDKN2A, and TP53. Patients without mutations in any of these genes were termed quadruple wild type (QuadWT). Clinical outcomes including median time to progression (TTP), median overall survival (OS), 6-month and 12-month OS, 6-month and 12-month without progression, ORR and disease control rate (DCR) were analyzed according to the mutational status of CDKN2A, TP53 and QuadWT.

Results: A total of 102 patients were included in this study of which 14 had mutations of CDKN2A (CDKN2Amut), 21 had TP53 mutations (TP53mut), and 12 were QuadWT. TP53mut, CDKN2Amut and QuadWT mutational status did not impact clinical outcomes including median TTP, median OS, 6-month and 12-month OS, 6-month and 12-month without progression, ORR and DCR. There was a trend towards improved median TTP and DCR in CDKN2Amut cohort and a trend towards worsened median TTP in the QuadWT cohort.

Conclusion: Cell cycle regulators such as TP53 and CDKN2A do not appear to significantly alter clinical outcomes when immune checkpoint inhibitors are used.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230306PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083309PMC
June 2020

Pilot evaluation of PD-1 inhibition in metastatic cancer patients with a history of liver transplantation: the Mayo Clinic experience.

J Gastrointest Oncol 2018 Dec;9(6):1054-1062

Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, USA.

Background: Patients with solid organ transplants (SOTs) have been excluded from programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitor clinical trials due to concern for allograft rejection. The use of immune checkpoint inhibitor therapy remains controversial in transplant patients.

Methods: A retrospective pilot evaluation was conducted to assess the safety and efficacy of PD-1 inhibitors in patients with liver transplantation (LT). The primary endpoint was the rate of allograft rejection. Secondary endpoints included overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Translational objectives included evaluation of tumor PD-L1, tumor infiltrating lymphocytes (TILs) and allograft PD-L1 expression.

Results: Seven metastatic cancer patients with a history of LT who received PD-1 inhibitor therapy were included [hepatocellular carcinoma (HCC), n=5; melanoma, n=2]. Rejection was observed in 2 of 7 patients. When rejection occurs it appears to be an early event with a median time to rejection of 24 days in our cohort. One patient achieved a complete response (CR), 3 patients had progressive disease (PD) and 3 patients discontinued therapy prior to restaging assessments. Two of five patients with available tissue had PD-L1 expression in the allograft and both developed rejection. One of five evaluable patients had abundant TILs. Two of five evaluable patients had PD-L1 tumor staining. The single patient with both abundant TILs and PD-L1 staining obtained a response. The median OS and PFS were 1.1 (0.3-21.1) and 1.8 (0.7-21.1) months, respectively.

Conclusions: In this pilot evaluation both preliminary efficacy (1 of 4) and allograft rejection (2 of 7) were exhibited in evaluable patients. Larger, prospective trials are needed to elucidate optimal patient selection.
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http://dx.doi.org/10.21037/jgo.2018.07.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286929PMC
December 2018

Emerging role of precision medicine in biliary tract cancers.

NPJ Precis Oncol 2018 3;2:21. Epub 2018 Oct 3.

1Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ USA.

Biliary tracts cancers (BTCs) are a diverse group of aggressive malignancies with an overall poor prognosis. Genomic characterization has uncovered many putative clinically actionable aberrations that can also facilitate the prognostication of patients. As such, comprehensive genomic profiling is playing a growing role in the clinical management of BTCs. Currently however, there is only one precision medicine approved by the US Food and Drug Administration (FDA) for the treatment of BTCs. Herein, we highlight the prevalence and prognostic, diagnostic, and predictive significance of recurrent mutations and other genomic aberrations with current clinical implications or emerging relevance to clinical practice. Some ongoing clinical trials, as well as future areas of exploration for precision oncology in BTCs are highlighted.
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http://dx.doi.org/10.1038/s41698-018-0064-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170410PMC
October 2018

Novel immunotherapy strategies for hepatobiliary cancers.

Immunotherapy 2018 09;10(12):1077-1091

Department of Medicine, Division of Hematology & Oncology, Mayo Clinic, Scottsdale, AZ 85259, USA.

Despite recent advancements in therapeutic options for advanced hepatobiliary cancers, there remains an unmet need for innovative systemic treatments. Immunotherapy has shown an ability to provide prolonged clinical benefit, but this benefit remains limited to a small subset of patients. Numerous ongoing endeavors are investigating novel immunotherapy concepts. Immunotherapies that have demonstrated clinical efficacy in hepatobiliary cancers include PD-1 inhibitor therapy and CTLA-4 inhibitor therapy. Novel immunotherapy concepts include targeting emerging checkpoint proteins, bispecific T-cell engagers, combinatorial trials with checkpoint inhibitors, oncolytic virotherapy and chimeric antigen receptor T cells. The goal for these new treatment strategies is to achieve a meaningful expansion of patients deriving prolonged clinical benefit from immunotherapy.
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http://dx.doi.org/10.2217/imt-2018-0024DOI Listing
September 2018

Oncolytic virotherapy in upper gastrointestinal tract cancers.

Oncolytic Virother 2017 23;7:13-24. Epub 2018 Mar 23.

Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ.

Upper gastrointestinal tract malignancies are among the most challenging cancers with regard to response to treatment and prognosis. Cancers of the esophagus, stomach, pancreas, liver, and biliary tree have dismal 5-year survival, and very modest improvements in this rate have been made in recent times. Oncolytic viruses are being developed to address these malignancies, with a focus on high safety profiles and low off-target toxicities. Each viral platform has evolved to enhance oncolytic potency and the clinical response to either single-agent viral therapy or combined viral treatment with radiotherapy and chemotherapy. A panel of genomic alterations, chimeric proteins, and pseudotyped capsids are the breakthroughs for vector success. This article revisits developments for each viral platform to each tumor type, in an attempt to achieve maximum tumor selectivity. From the bench to clinical trials, the scope of this review is to highlight the beginnings of translational oncolytic virotherapy research in upper gastrointestinal tract malignancies and provide a bioengineering perspective of the most promising platforms.
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http://dx.doi.org/10.2147/OV.S161397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870634PMC
March 2018

Novel targeted therapy strategies for biliary tract cancers and hepatocellular carcinoma.

Future Oncol 2018 Mar 20;14(6):553-566. Epub 2018 Feb 20.

Division of Hematology Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA.

Worldwide hepatobiliary cancers are the second leading cause of cancer related death. Despite their relevance, hepatobiliary cancers have a paucity of approved systemic therapy options. However, there are a number of emerging therapeutic biomarkers and therapeutic concepts that show promise. In hepatocellular carcinoma, nivolumab appears particularly promising and recently received US FDA approval. In intrahepatic cholangiocarcinoma, therapies targeting FGFR2 and IDH1 and immune checkpoint inhibitors are the furthest along and generating the most excitement. There are additional biomarkers that merit further exploration in hepatobiliary cancers including FGF19, ERRFI1, TERT, BAP1, BRAF, CDKN2A, tumor mutational burden and ERBB2 (HER2/neu). Development of new and innovative therapies would help address the unmet need for effective systemic therapies in advanced and metastatic hepatobiliary cancers.
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http://dx.doi.org/10.2217/fon-2017-0451DOI Listing
March 2018

Oncolytic virus delivery: from nano-pharmacodynamics to enhanced oncolytic effect.

Oncolytic Virother 2017 8;6:39-49. Epub 2017 Nov 8.

Division of Hematology Oncology, Department of Medicine, Mayo Clinic, Scottsdale.

With the advancement of a growing number of oncolytic viruses (OVs) to clinical development, drug delivery is becoming an important barrier to overcome for optimal therapeutic benefits. Host immunity, tumor microenvironment and abnormal vascularity contribute to inefficient vector delivery. A number of novel approaches for enhanced OV delivery are under evaluation, including use of nanoparticles, immunomodulatory agents and complex viral-particle ligands along with manipulations of the tumor microenvironment. This field of OV delivery has quickly evolved to bioengineering of complex nanoparticles that could be deposited within the tumor using minimal invasive image-guided delivery. Some of the strategies include ultrasound (US)-mediated cavitation-enhanced extravasation, magnetic viral complexes delivery, image-guided infusions with focused US and targeting photodynamic virotherapy. In addition, strategies that modulate tumor microenvironment to decrease extracellular matrix deposition and increase viral propagation are being used to improve tumor penetration by OVs. Some involve modification of the viral genome to enhance their tumoral penetration potential. Here, we highlight the barriers to oncolytic viral delivery, and discuss the challenges to improving it and the perspectives of establishing new modes of active delivery to achieve enhanced oncolytic effects.
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http://dx.doi.org/10.2147/OV.S145262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687448PMC
November 2017

Mycobacterium avium complex empyema in a patient with interferon gamma autoantibodies.

Hawaii J Med Public Health 2014 Sep;73(9 Suppl 1):15-7

Internal Medicine Residency Program, John A. Burns School of Medicine, University of Hawai'i, Honolulu, HI (TTD).

Interferon gamma (IFN-γ) autoantibodies are a relatively recently discovered clinical entity, which have been shown to be associated with disseminated non-tuberculous mycobacterial (NTM) infections and other opportunistic infections. Interestingly, isolated NTM infections (without disseminated NTM infection) have not been shown to be a good predictor of the presence of IFN-γ autoantibodies. This case describes an isolated NTM empyema in a patient with IFN-γ autoantibodies and makes the argument that the development of an NTM empyema in a patient with no known immunodeficiency should prompt consideration for IFN-γ testing. Additionally, this case underscores the importance for clinicians to recognize that an unusual infection without the typical cause of impairment in immunity should prompt a more thorough investigation of the patient's immune system.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175962PMC
September 2014