Publications by authors named "Cassian Yee"

97 Publications

Incidence, predictors, and survival impact of acute kidney injury in patients with melanoma treated with immune checkpoint inhibitors: a 10-year single-institution analysis.

Oncoimmunology 2021 May 23;10(1):1927313. Epub 2021 May 23.

Section of Nephrology, Division of Internal Medicine, Section of Nephrology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

: The incidence of renal immune-related adverse events (irAEs) is reported to be 3.8%, with varied definitions of acute kidney injury (AKI). This study reports a 10-year experience at MD Anderson Cancer Center of patients diagnosed with melanoma and treated with immune checkpoint inhibitors (ICIs) and evaluated the incidence of AKI, associated factors, and its association with overall survival. : A retrospective chart review (2010-2019) of all patients with melanoma treated with ipilimumab, nivolumab, pembrolizumab, or atezolizumab was performed. All available serum creatinine data were extracted and used to calculate the estimated GFR (eGFR) using the CKD Epi equation, and to diagnose AKI using the two KDIGO (Kidney Disease: Improving Global Outcomes) criteria for defining stage I AKI in 1664 unique patients. Cumulative incidence rates of AKI after initiation of ICIs were calculated in the presence of death as a competing risk. The effects of covariates on the cumulative incidence function of AKI were evaluated in a univariant and multivariable analysis. Overall survival was estimated by Kaplan-Meier method in accordance to the occurrence of AKI. : The incidence of AKI by definitions 1a and 1b were 3.49% and 3.33%, respectively. After adjudication, AKI attributable to ICI was 58% and 65% of the overall incidence of AKI in each definition respectively. Increasing age was associated with decreased risk of AKI. Asian race was associated with a higher risk of AKI. Comorbidities were not associated with increased risk of AKI while use of proton pump inhibitors (PPI), ipilimumab or ICI combinations were significantly associated with AKI. AKI was not significantly associated with overall survival. Immune-related adverse events (irAEs) occurred in 30% of patients with AKI but their incidence was not different in patients with AKI attributable to ICI versus other AKI. : In a large population of patients with melanoma treated with ICIs, an accurate documentation of AKI in setting of ICI use and predictors associated is presented. AKI following ICI use is infrequent, not associated with mortality, and associated with the use of ipilimumab, ICI combinations and PPIs.
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http://dx.doi.org/10.1080/2162402X.2021.1927313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158025PMC
May 2021

Hypoxia acts as an environmental cue for the human tissue-resident memory T cell differentiation program.

JCI Insight 2021 May 24;6(10). Epub 2021 May 24.

Department of Melanoma Medical Oncology, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, USA.

Tissue-resident memory T cells (TRM) provide frontline defense against infectious diseases and contribute to antitumor immunity; however, aside from the necessity of TGF-β, knowledge regarding TRM-inductive cues remains incomplete, particularly for human cells. Oxygen tension is an environmental cue that distinguishes peripheral tissues from the circulation, and here, we demonstrate that differentiation of human CD8+ T cells in the presence of hypoxia and TGF-β1 led to the development of a TRM phenotype, characterized by a greater than 5-fold increase in CD69+CD103+ cells expressing human TRM hallmarks and enrichment for endogenous human TRM gene signatures, including increased adhesion molecule expression and decreased expression of genes involved in recirculation. Hypoxia and TGF-β1 synergized to produce a significantly larger population of TRM phenotype cells than either condition alone, and comparison of these cells from the individual and combination conditions revealed distinct phenotypic and transcriptional profiles, indicating a programming response to milieu rather than a mere expansion. Our findings identify a likely previously unreported cue for the TRM differentiation program and can enable facile generation of human TRM phenotype cells in vitro for basic studies and translational applications such as adoptive cellular therapy.
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http://dx.doi.org/10.1172/jci.insight.138970DOI Listing
May 2021

Randomized phase II trial of lymphodepletion plus adoptive cell transfer of tumor-infiltrating lymphocytes, with or without dendritic cell vaccination, in patients with metastatic melanoma.

J Immunother Cancer 2021 May;9(5)

Melanoma Medical Onoclogy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Background: The adoptive transfer of tumor-infiltrating lymphocytes (TIL) has demonstrated robust efficacy in metastatic melanoma patients. Tumor antigen-loaded dendritic cells (DCs) are believed to optimally activate antigen-specific T lymphocytes. We hypothesized that the combined transfer of TIL, containing a melanoma antigen recognized by T cells 1 (MART-1) specific population, with MART-1-pulsed DC will result in enhanced proliferation and prolonged survival of transferred MART-1 specific T cells in vivo ultimately leading to improved clinical responses.

Design: We tested the combination of TIL and DC in a phase II clinical trial of patients with advanced stage IV melanoma. HLA-A0201 patients whose early TIL cultures demonstrated reactivity to MART-1 peptide were randomly assigned to receive TIL alone or TIL +DC pulsed with MART-1 peptide. The primary endpoint was to evaluate the persistence of MART-1 TIL in the two arms. Secondary endpoints were to evaluate clinical response and survival.

Results: Ten patients were given TIL alone while eight patients received TIL+DC vaccine. Infused MART-1 reactive CD8 TIL were tracked in the blood over time by flow cytometry and results show good persistence in both arms, with no difference in the persistence of MART-1 between the two arms. The objective response rate was 30% (3/10) in the TIL arm and 50% (4/8) in the TIL+DC arm. All treatments were well tolerated.

Conclusions: The combination of TIL +DC showed no difference in the persistence of MART-1 TIL compared with TIL therapy alone. Although more patients showed a clinical response to TIL+DC therapy, this study was not powered to resolve differences between groups.

Trial Registration Number: NCT00338377.
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http://dx.doi.org/10.1136/jitc-2021-002449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144048PMC
May 2021

IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy.

J Immunother Cancer 2021 May;9(5)

Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA

Background: Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1-specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression.

Method: We performed a phase I clinical trial evaluating the safety of NY-ESO-1-specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15.

Results: Four patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1-specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor-based products at other centers.

Conclusions: ETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1-specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression.
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http://dx.doi.org/10.1136/jitc-2020-002232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108691PMC
May 2021

Hypoxia-Driven HIF-1α Activation Reprograms Pre-Activated NK Cells towards Highly Potent Effector Phenotypes via ERK/STAT3 Pathways.

Cancers (Basel) 2021 Apr 15;13(8). Epub 2021 Apr 15.

Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Korea.

NK cells are the predominant innate lymphocyte subsets specialized to kill malignant tumor cells. In patients with advanced cancer, hypoxic stress shapes NK cells toward tumor-resistant and immunosuppressive phenotypes, hence a strategy to restore NK function is critical for successful tumor immunotherapy. Here, we present evidence that pre-activation and subsequent HIF-1α-dependent metabolic shift of NK cells from oxidative phosphorylation into glycolysis are keys to overcome hypoxia-mediated impairment in NK cell survival, proliferation, and tumor cytotoxicity. Specifically, exposing NK cells to 7-9 days of normoxic culture followed by a pO of 1.5% hypoxia led to a highly potent effector phenotype via HIF-1α stabilization and upregulation of its target genes, , , , , and . RNA sequencing and network analyses revealed that concomitant reduction of p21/p53 apoptotic pathways along with upregulation of cell cycle-promoting genes, , , and downregulation of cell cycle-arrest genes, , , and were accountable for superior expansion of NK cells via ERK/STAT3 activation. Furthermore, HIF-1α-dependent upregulation of the NKp44 receptor in hypoxia-exposed NK cells resulted in increased killing against K562, CEM, and A375 tumor targets both in-vitro and in-vivo tumor clearance assays. Therefore, hypoxic exposure on pre-activated proliferating NK cells triggered HIF-1α-dependent pathways to initiate coordinated regulation of cell cycle, apoptosis, and cytotoxicity at the global gene transcription level. Our results uncover a previously unidentified role of HIF-1α-mediated metabolic reprogramming that can reverse impaired NK effector phenotypes to generate requisite numbers of functionally robust NK cells for adoptive cellular therapy for clinical evaluation.
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http://dx.doi.org/10.3390/cancers13081904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071270PMC
April 2021

Infliximab for the treatment of patients with checkpoint inhibitor-associated acute tubular interstitial nephritis.

Oncoimmunology 2021 02 2;10(1):1877415. Epub 2021 Feb 2.

Section of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Acute tubular interstitial nephritis (ATIN) is the most frequently reported pathology in patients with checkpoint inhibitor (CPI) induced acute kidney injury (AKI). Glucocorticoid (GC) therapy and discontinuation of CPI are the mainstay of treatment to prevent permanent renal dysfunction and dialysis. However, less than 50% of patients have complete kidney recovery and relapse of ATIN can occur. Infliximab is effective in treating other immune-related adverse events but its use for the treatment of CPI-ATIN is not well established. We report the first retrospective study examining the steroid-sparing potential of infliximab in achieving durable and complete renal recovery for patients with CPI-ATIN. Data were collected from medical records of patients diagnosed with CPI-AKI with a kidney biopsy or clinical diagnosis of ATIN that was managed with GC and infliximab. Infliximab-containing regimens were used to treat 10 patients with CPI-ATIN. Four patients relapsing after GC therapy achieved durable and complete renal recovery, four patients experienced partial renal recovery, and two patients showed no improvement in kidney function. This is the first study evaluating clinical outcomes using an infliximab-containing regimen for treatment of relapsed CPI-ATIN in patients or patients failing to achieve complete response after primary therapy. Our data suggest that infliximab may be a treatment option for achieving durable and complete renal recovery in this patient population and represents a potential steroid-sparing strategy in challenging cases of CPI-ATIN. Rigorous clinical studies are warranted to evaluate the risk-benefit analysis for infliximab usage in CPI-ATIN patients.
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http://dx.doi.org/10.1080/2162402X.2021.1877415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872057PMC
February 2021

Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators.

J Immunother Cancer 2021 Feb;9(2)

Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA

Background: Despite approval of immunotherapy for a wide range of cancers, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conventional methods to systematically evaluate the potential of tumor intrinsic factors to act as immune regulators in patients with cancer.

Methods: To identify immunosuppressive mechanisms in non-responders to cancer immunotherapy in an unbiased manner, we performed genome-wide CRISPR immune screens and integrated our results with multi-omics clinical data to evaluate the role of tumor intrinsic factors in regulating two rate-limiting steps of cancer immunotherapy, namely, T cell tumor infiltration and T cell-mediated tumor killing.

Results: Our studies revealed two distinct types of immune resistance regulators and demonstrated their potential as therapeutic targets to improve the efficacy of immunotherapy. Among them, PRMT1 and RIPK1 were identified as a dual immune resistance regulator and a cytotoxicity resistance regulator, respectively. Although the magnitude varied between different types of immunotherapy, genetically targeting and sensitized tumors to T-cell killing and anti-PD-1/OX40 treatment. Interestingly, a RIPK1-specific inhibitor enhanced the antitumor activity of T cell-based and anti-OX40 therapy, despite limited impact on T cell tumor infiltration.

Conclusions: Collectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations.
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http://dx.doi.org/10.1136/jitc-2020-001819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887353PMC
February 2021

Vestigial-like 1 is a shared targetable cancer-placenta antigen expressed by pancreatic and basal-like breast cancers.

Nat Commun 2020 10 21;11(1):5332. Epub 2020 Oct 21.

Department of Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA.

Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regressions by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from 35 PDAC patient tumors. This identified a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1) as a putative TAA demonstrating overexpression in multiple tumor types and low or absent expression in essential normal tissues. Here we show that VGLL1-specific CTLs expanded from the blood of a PDAC patient could recognize and kill in an antigen-specific manner a majority of HLA-A*0101 allogeneic tumor cell lines derived not only from PDAC, but also bladder, ovarian, gastric, lung, and basal-like breast cancers. Gene expression profiling reveals VGLL1 as a member of a unique group of cancer-placenta antigens (CPA) that may constitute immunotherapeutic targets for patients with multiple cancer types.
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http://dx.doi.org/10.1038/s41467-020-19141-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577998PMC
October 2020

Immune checkpoint inhibitor associated reactivation of primary membranous nephropathy responsive to rituximab.

J Immunother Cancer 2020 10;8(2)

Section of Nephrology, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

The same mechanisms that mediate antitumor immunity from checkpoint inhibitors (CPIs) can also lead to unintended targeting of normal tissues, characterized as immune-related adverse events (irAEs). Those with pre-existing autoimmune disease are believed to be particularly vulnerable for exacerbating underlying autoimmunity or inducing severe irAEs. We report the first case of CPI-associated reactivation of primary membranous nephropathy (MN) in a patient with pleural mesothelioma responding to immunotherapy. Due to its specificity in targeting B-lymphocytes, rituximab was used to treat primary MN with the expectation that this would not interfere with the benefits gained from T cell-mediated antitumor immunity. Rituximab was effective in treating CPI-associated reactivation of MN, and the patient was successfully rechallenged with nivolumab and maintained stable kidney function and sustained clinical antitumor effect. While exacerbation of pre-existing autoimmune diseases from CPIs is common, therapy for autoimmune reactivation can be rationally directed by an understanding of the immunosuppressive mechanism with goals of cancer treatment.
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http://dx.doi.org/10.1136/jitc-2020-001287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537330PMC
October 2020

LC3B upregulation by NANOG promotes immune resistance and stem-like property through hyperactivation of EGFR signaling in immune-refractory tumor cells.

Autophagy 2020 Aug 14:1-20. Epub 2020 Aug 14.

Department of Biochemistry & Molecular Biology, Department of Biomedical Science, Korea University College of Medicine, Seoul, South Korea.

Immune selection drives tumor cells to acquire refractory phenotypes. We previously demonstrated that cytotoxic T lymphocyte (CTL)-mediated immune pressure enriches NANOG tumor cells with stem-like and immune-refractory properties that make them resistant to CTLs. Here, we report that the emergence of refractory phenotypes is highly associated with an aberrant macroautophagic/autophagic state of the NANOG tumor cells and that the autophagic phenotype arises through transcriptional induction of by NANOG. Furthermore, we found that upregulation of LC3B expression contributes to an increase in EGF secretion. The subsequent hyperactivation of EGFR-AKT signaling rendered NANOG tumor cells resistant to CTL killing. The NANOG-LC3B-p-EGFR axis was preserved across various types of human cancer and correlated negatively with the overall survival of cervical cancer patients. Inhibition of LC3B in immune-refractory tumor models rendered tumors susceptible to adoptive T-cell transfer, as well as PDCD1/PD-1 blockade, and led to successful, long-term control of the disease. Thus, our findings demonstrate a novel link among immune-resistance, stem-like phenotypes, and LC3B-mediated autophagic secretion in immune-refractory tumor cells, and implicate the LC3B-p-EGFR axis as a central molecular target for controlling NANOG immune-refractory cancer.

Abbreviations: ACTB: actin beta; ATG7: autophagy related 7; BafA1: bafilomycin A; CASP3: caspase 3; CFSE: carboxyfluorescein succinimidyl ester; ChIP: chromatin immunoprecipitation; CI: confidence interval; CIN: cervical intraepithelial neoplasia; CSC: cancer stem cell; CTL: cytotoxic T lymphocyte; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; FIGO: International Federation of Gynecology and Obstetrics; GFP: green fluorescent protein; GZMB: granzyme B; HG-CIN: high-grade CIN; IHC: immunohistochemistry; LG-CIN: low-grade CIN; LN: lymph node; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCL1: myeloid cell leukemia sequence 1; MLANA/MART-1: melanoma antigen recognized by T cells 1; MUT: mutant; NANOG: Nanog homeobox; PDCD1/PD-1: programmed cell death 1; PMEL/gp100: premelanosome protein; RTK: receptor tyrosine kinase; TMA: tissue microarray; WT: wild type.
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http://dx.doi.org/10.1080/15548627.2020.1805214DOI Listing
August 2020

Single-dose intranasal vaccination elicits systemic and mucosal immunity against SARS-CoV-2.

bioRxiv 2020 Jul 23. Epub 2020 Jul 23.

A safe and durable vaccine is urgently needed to tackle the COVID19 pandemic that has infected >15 million people and caused >620,000 deaths worldwide. As with other respiratory pathogens, the nasal compartment is the first barrier that needs to be breached by the SARS-CoV-2 virus before dissemination to the lung. Despite progress at remarkable speed, current intramuscular vaccines are designed to elicit systemic immunity without conferring mucosal immunity. We report the development of an intranasal subunit vaccine that contains the trimeric or monomeric spike protein and liposomal STING agonist as adjuvant. This vaccine induces systemic neutralizing antibodies, mucosal IgA responses in the lung and nasal compartments, and T-cell responses in the lung of mice. Single-cell RNA-sequencing confirmed the concomitant activation of T and B cell responses in a germinal center-like manner within the nasal-associated lymphoid tissues (NALT), confirming its role as an inductive site that can lead to long-lasting immunity. The ability to elicit immunity in the respiratory tract has can prevent the initial establishment of infection in individuals and prevent disease transmission across humans.
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http://dx.doi.org/10.1101/2020.07.23.212357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386485PMC
July 2020

Spatially resolved analyses link genomic and immune diversity and reveal unfavorable neutrophil activation in melanoma.

Nat Commun 2020 04 15;11(1):1839. Epub 2020 Apr 15.

Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Complex tumor microenvironmental (TME) features influence the outcome of cancer immunotherapy (IO). Here we perform immunogenomic analyses on 67 intratumor sub-regions of a PD-1 inhibitor-resistant melanoma tumor and 2 additional metastases arising over 8 years, to characterize TME interactions. We identify spatially distinct evolution of copy number alterations influencing local immune composition. Sub-regions with chromosome 7 gain display a relative lack of leukocyte infiltrate but evidence of neutrophil activation, recapitulated in The Cancer Genome Atlas (TCGA) samples, and associated with lack of response to IO across three clinical cohorts. Whether neutrophil activation represents cause or consequence of local tumor necrosis requires further study. Analyses of T-cell clonotypes reveal the presence of recurrent priming events manifesting in a dominant T-cell clonotype over many years. Our findings highlight the links between marked levels of genomic and immune heterogeneity within the physical space of a tumor, with implications for biomarker evaluation and immunotherapy response.
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http://dx.doi.org/10.1038/s41467-020-15538-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160105PMC
April 2020

Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy.

J Immunother Cancer 2020 04;8(1)

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

Background: Adoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a 'cold' tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS.

Case Presentation: We launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns.

Conclusion: We describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion.

Trial Registration Numbers: NCT04177021, NCT01957709, and NCT03063632.
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http://dx.doi.org/10.1136/jitc-2019-000247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254118PMC
April 2020

Histone Deacetylase Inhibitors and IL21 Cooperate to Reprogram Human Effector CD8 T Cells to Memory T Cells.

Cancer Immunol Res 2020 06 25;8(6):794-805. Epub 2020 Mar 25.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Clinical response rates after adoptive cell therapy (ACT) are highly correlated with persistence of the infused T cells. However, antigen-specific T cells found in tumor sites are often well-differentiated effector cells with limited persistence. Central memory CD8 T cells, capable of self-renewal, represent desirable ACT products. We report here that exposure to a histone deacetylase inhibitor (HDACi) and IL21 could reprogram differentiated human CD8 T cells into central memory-like T cells. Dedifferentiation of CD8 T cells was initiated by increased H3 acetylation and chromatin accessibility at the promoter region. This led to IL21-mediated pSTAT3 binding to the region, and subsequent upregulation of surface CD28 and CD62L (markers of central memory T cells). The reprogrammed cells exhibited enhanced proliferation in response to both IL2 and IL15, and a stable memory-associated transcriptional signature (increased and ). Our findings support the application of IL21 and HDACi for the generation of highly persistent T-cell populations that can augment the efficacy of adoptively transferred T cells.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269845PMC
June 2020

Combination of PD-1 Inhibitor and OX40 Agonist Induces Tumor Rejection and Immune Memory in Mouse Models of Pancreatic Cancer.

Gastroenterology 2020 07 14;159(1):306-319.e12. Epub 2020 Mar 14.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas; The University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences, Houston, Texas. Electronic address:

Background & Aims: Advanced pancreatic ductal adenocarcinoma (PDAC) is resistant to therapy, including immune checkpoint inhibitors. We evaluated the effects of a neutralizing antibody against programmed cell death 1 (PD-1) and an agonist of OX40 (provides a survival signal to activated T cells) in mice with pancreatic tumors.

Methods: We performed studies in C57BL/6 mice (controls), Kras;Trp53;Pdx-1-Cre (KPC) mice, and mice with orthotopic tumors grown from Panc02 cells, Kras;P53;PDX-1-Cre;Luciferase (KPC-Luc) cells, or mT4 cells. After tumors developed, mice were given injections of control antibody or anti-OX40 and/or anti-PD-1 antibody. Some mice were then given injections of antibodies against CD8, CD4, or NK1.1 to deplete immune cells, and IL4 or IL7RA to block cytokine signaling. Bioluminescence imaging was used to monitor tumor growth. Tumor tissues collected and single-cell suspensions were analyzed by time of flight mass spectrometry analysis. Mice that were tumor-free 100 days after implantation of orthotopic tumors were rechallenged with PDAC cells (KPC-Luc or mT4) and survival was measured. Median levels of PD-1 and OX40 mRNAs in PDACs were determined from The Cancer Genome Atlas and compared with patient survival times.

Results: In mice with orthotopic tumors, all those given control antibody or anti-PD-1 died within 50 days, whereas 43% of mice given anti-OX40 survived for 225 days; almost 100% of mice given the combination of anti-PD-1 and anti-OX40 survived for 225 days, and tumors were no longer detected. KPC mice given control antibody, anti-PD-1, or anti-OX40 had median survival times of 50 days or less, whereas mice given the combination of anti-PD-1 and anti-OX40 survived for a median 88 days. Mice with orthotopic tumors that were given the combination of anti-PD-1 and anti-OX40 and survived 100 days were rechallenged with a second tumor; those rechallenged with mT4 cells survived an additional median 70 days and those rechallenged with KPC-Luc cells survived long term, tumor free. The combination of anti-PD-1 and anti-OX40 did not slow tumor growth in mice with antibody-mediated depletion of CD4+ T cells. Mice with orthotopic tumors given the combination of anti-PD-1 and anti-OX40 that survived after complete tumor rejection were rechallenged with KPC-Luc cells; those with depletion of CD4+ T cells before the rechallenge had uncontrolled tumor growth. Furthermore, KPC orthotopic tumors from mice given the combination contained an increased number of CD4+ T cells that expressed CD127 compared with mice given control antibody. The combination of agents reduced the proportion of T-regulatory and exhausted T cells and decreased T-cell expression of GATA3; tumor size was negatively associated with numbers of infiltrating CD4+ T cells, CD4+CD127+ T cells, and CD8+CD127+ T cells, and positively associated with numbers of CD4+PD-1+ T cells, CD4+CD25+ T cells, and CD8+PD-1+ T cells. PDACs with high levels of OX40 and low levels of PD-1 were associated with longer survival times of patients.

Conclusions: Pancreatic tumors appear to evade the immune response by inducing development of immune-suppressive T cells. In mice, the combination of anti-PD-1 inhibitory and anti-OX40 agonist antibodies reduces the proportion of T-regulatory and exhausted T cells in pancreatic tumors and increases numbers of memory CD4+ and CD8+ T cells, eradicating all detectable tumor. This information can be used in development of immune-based combination therapies for PDAC.
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http://dx.doi.org/10.1053/j.gastro.2020.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387152PMC
July 2020

HSP90A inhibition promotes anti-tumor immunity by reversing multi-modal resistance and stem-like property of immune-refractory tumors.

Nat Commun 2020 Jan 28;11(1):562. Epub 2020 Jan 28.

Department of Biochemistry & Molecular Biology, Korea University College of Medicine, Seoul, Korea.

Cancer immunotherapy has emerged as a promising cancer treatment. However, the presence of immune-refractory tumor cells limits its clinical success by blocking amplification of anti-tumor immunity. Previously, we found that immune selection by immunotherapy drives the evolution of tumors toward multi-modal resistant and stem-like phenotypes via transcription induction of AKT co-activator TCL1A by NANOG. Here, we report a crucial role of HSP90A at the crossroads between NANOG-TCL1A axis and multi-aggressive properties of immune-edited tumor cells by identifying HSP90AA1 as a NANOG transcriptional target. Furthermore, we demonstrate that HSP90A potentiates AKT activation through TCL1A-stabilization, thereby contributing to the multi-aggressive properties in NANOG tumor cells. Importantly, HSP90 inhibition sensitized immune-refractory tumor to adoptive T cell transfer as well as PD-1 blockade, and re-invigorated the immune cycle of tumor-reactive T cells. Our findings implicate that the HSP90A-TCL1A-AKT pathway ignited by NANOG is a central molecular axis and a potential target for immune-refractory tumor.
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http://dx.doi.org/10.1038/s41467-019-14259-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987099PMC
January 2020

Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma.

Cancer Discov 2020 03 8;10(3):440-459. Epub 2020 Jan 8.

Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.

mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by mutation are direct targets of the BCL6-HDAC3 onco-repressor complex. Accordingly, we show that HDAC3-selective inhibitors reverse -mutant aberrant epigenetic programming, resulting in: (i) growth inhibition of lymphoma cells through induction of BCL6 target genes such as and (ii) restoration of immune surveillance due to induction of BCL6-repressed IFN pathway and antigen-presenting genes. By reactivating these genes, exposure to HDAC3 inhibitors restored the ability of tumor-infiltrating lymphocytes to kill DLBCL cells in an MHC class I and II-dependent manner, and synergized with PD-L1 blockade in a syngeneic model . Hence, HDAC3 inhibition represents a novel mechanism-based immune epigenetic therapy for -mutant lymphomas. SIGNIFICANCE: We have leveraged the molecular characterization of different types of mutations to define a rational approach for targeting these mutations through selective inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting synthetic vulnerabilities in -mutant cells in tandem with promoting antitumor immunity..
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http://dx.doi.org/10.1158/2159-8290.CD-19-0116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275250PMC
March 2020

Immune checkpoint inhibitor related myasthenia gravis: single center experience and systematic review of the literature.

J Immunother Cancer 2019 11 21;7(1):319. Epub 2019 Nov 21.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Myasthenia gravis (MG) is a rare but life-threatening adverse event of immune checkpoint inhibitors (ICI). Given the limited evidence, data from a large cohort of patients is needed to aid in recognition and management of this fatal complication.

Methods: We reviewed our institutional databases to identify patients who had cancer and MG in the setting of ICI. We systematically reviewed the literature through August 2018 to identify all similar reported patients. We collected data on clinical and diagnostic features, management, and outcomes of these cases.

Results: Sixty-five patients were identified. Median age was 73 years; 42 (65%) were males, 31 (48%) had metastatic melanoma, and 13 (20%) had a preexisting MG before ICI initiation. Most patients received anti-PD-1 (82%). Sixty-three patients (97%) developed ICI-related MG (new onset or disease flare) after a median of 4 weeks (1 to 16 weeks) of ICI initiation. Twenty-four patients (37%) experienced concurrent myositis, and respiratory failure occurred in 29 (45%). ICI was discontinued in 61 patients (97%). Death was reported in 24 patients (38%); 15 (23%) due to MG complication. A better outcome was observed in patients who received intravenous immunoglobulin (IVIG) or plasmapheresis (PLEX) as first-line therapy than in those who received steroids alone (95% vs 63% improvement of MG symptoms, p = 0.011).

Conclusions: MG is a life-threatening adverse event of acute onset and rapid progression after ICI initiation. Early use of IVIG or PLEX, regardless of initial symptoms severity, may lead to better outcomes than steroids alone. Our data suggest the need to reassess the current recommendations for management of ICI-related MG until prospective longitudinal studies are conducted to establish the ideal management approach for these patients.
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http://dx.doi.org/10.1186/s40425-019-0774-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868691PMC
November 2019

CD160 serves as a negative regulator of NKT cells in acute hepatic injury.

Nat Commun 2019 07 22;10(1):3258. Epub 2019 Jul 22.

Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, 02841, Republic of Korea.

CD160 and BTLA both bind to herpes virus entry mediator. Although a negative regulatory function of BTLA in natural killer T (NKT) cell activation has been reported, whether CD160 is also involved is unclear. By analyzing CD160 mice and mixed bone marrow chimeras, we show that CD160 is not essential for NKT cell development. However, CD160 mice exhibit severe liver injury after in vivo challenge with α-galactosylceramide (α-GalCer). Moreover, CD160 mice are more susceptible to Concanavalin A challenge, and display elevated serum AST and ALT levels, hyperactivation of NKT cells, and enhanced IFN-γ, TNF, and IL-4 production. Lastly, inhibition of BTLA by anti-BTLA mAb aggravates α-GalCer-induced hepatic injury in CD160 mice, suggesting that both CD160 and BTLA serve as non-overlapping negative regulators of NKT cells. Our data thus implicate CD160 as a co-inhibitory receptor that delivers antigen-dependent signals in NKT cells to dampen cytokine production during early innate immune activation.
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http://dx.doi.org/10.1038/s41467-019-10320-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646315PMC
July 2019

Systemic Interferon-γ Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors: Results of a Phase 0 Clinical Trial.

Cancer Immunol Res 2019 08 6;7(8):1237-1243. Epub 2019 Jun 6.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Interferon-γ (IFNγ) has been studied as a cancer treatment with limited evidence of clinical benefit. However, it could play a role in cancer immunotherapy combination treatments. Despite high expression of immunogenic cancer-testis antigens, synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) have a cold tumor microenvironment (TME), with few infiltrating T cells and low expression of major histocompatibility complex class I (MHC-I). We hypothesized that IFNγ treatment could drive inflammation in a cold TME, facilitating further immunotherapy. We conducted a phase 0 clinical trial treating 8 SS or MRCL patients with weekly systemic IFNγ. We performed pre- and posttreatment biopsies. IFNγ changed the SS and MRCL TME, inducing tumor-surface MHC-I expression and significant T-cell infiltration ( < 0.05). Gene-expression analysis suggested increased tumor antigen presentation and less exhausted phenotypes of the tumor-infiltrating T cells. Newly emergent antigen-specific humoral and/or T-cell responses were found in 3 of 7 evaluable patients. However, increased expression of PD-L1 was observed on tumor-infiltrating myeloid cells and in some cases tumor cells. These findings suggest that systemic IFNγ used to convert SS and MRCL into "hot" tumors will work in concert with anti-PD-1 therapy to provide patient benefit.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677581PMC
August 2019

CTL-mediated immunotherapy can suppress SHIV rebound in ART-free macaques.

Nat Commun 2019 05 21;10(1):2257. Epub 2019 May 21.

Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.

A major barrier to human immunodeficiency virus (HIV) cure is the existence of viral reservoirs that lead to viral rebound following discontinuation of antiretroviral therapy (ART). We postulate that enhancing cytotoxic T lymphocytes (CTL) targeting conserved envelope (Env) regions can eliminate HIV infected cells in latency. Here, we evaluate the use of adoptively transferred HIV vaccine-induced subtype C Env-specific CTLs in a macaque subtype B simian-human immunodeficiency virus (SHIV) model to determine whether plasma viremia can be controlled after ART interruption. We demonstrate that adoptive cellular therapy (ACT) using autologous Env-specific T cells augmented by therapeutic vaccination can suppress ART-free viral rebound in the SHIV model. Furthermore, phenotypic and functional characterization of adoptively transferred cells in ACT-responsive and nonresponsive animals support a critical role for cross-reactive central memory T cells in viremia control. Our study offers an approach to potentiate immunological suppression of HIV in the absence of antiviral drugs.
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http://dx.doi.org/10.1038/s41467-019-09725-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529452PMC
May 2019

An Update on Adoptive T-Cell Therapy and Neoantigen Vaccines.

Am Soc Clin Oncol Educ Book 2019 Jan 17;39:e70-e78. Epub 2019 May 17.

4 Center for Cancer Research, National Cancer Institute, Bethesda, MD.

Adoptive T-cell therapy using tumor-infiltrating lymphocytes (TILs) has demonstrated long-lasting antitumor activity in select patients with advanced melanoma. Cancer vaccines have been used for many decades and have shown some promise but overall relatively modest clinical activity across cancers. Technological advances in genome sequencing capabilities and T-cell engineering have had substantial impact on both adoptive cell therapy and the cancer vaccine field. The ability to identify neoantigens-a class of tumor antigens that is truly tumor specific and encoded by tumor mutations through rapid and relatively inexpensive next-generation sequencing-has already demonstrated the critical importance of these antigens as targets of antitumor-specific T-cell responses in the context of immune checkpoint blockade and other immunotherapies. Therapeutically targeting these antigens with either adoptive T-cell therapy or vaccine approaches has demonstrated early promise in the clinic in patients with advanced solid tumors. Chimeric antigen receptor (CAR) T cells, which are engineered by fusing an antigen-specific, single-chain antibody (scFv) with signaling molecules of the T-cell receptor (TCR)/CD3 complex creating an antibody-like structure on T cells that recognizes antigens independently of major histocompatibility complex (MHC) molecules, have demonstrated remarkable clinical activity in patients with advanced B-cell malignancies, leading to several approvals by the U.S. Food and Drug Administration (FDA).
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http://dx.doi.org/10.1200/EDBK_238001DOI Listing
January 2019

MAGE-A3 is a Clinically Relevant Target in Undifferentiated Pleomorphic Sarcoma/Myxofibrosarcoma.

Cancers (Basel) 2019 May 15;11(5). Epub 2019 May 15.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.

Melanoma-associated antigen 3 (MAGE-A3) expression is generally restricted to the placenta and germline cells of the testis, but it may also be expressed in sarcoma and other cancers and is associated with poor prognosis. Immunotherapy approaches targeting MAGE-A3 in other cancers have shown mixed results in the clinic, however, use of cancer testis antigens such as MAGE-A3 may have therapeutic value in the treatment of soft tissue sarcomas. Based on the recent success of anti-programmed death-1 (PD-1) therapy in undifferentiated pleomorphic sarcoma, we hypothesize that MAGE-A3-based immunotherapies may also provide benefits in this sarcoma type. We analyzed MAGE-A3 expression of sarcoma subtypes available in the Cancer Genome Atlas and Cancer Cell Line Encyclopedia and show that undifferentiated pleomorphic sarcoma/myxofibrosarcoma (UPS/MFS) expresses this potential target gene. We have identified high protein expression by tissue microarray of 106 UPS cores. We also found that high MAGE-A3 mRNA and protein expression is associated with worse overall survival in UPS/MFS. Furthermore, our results show no human leukocyte antigen (HLA) expression loss and relatively high lymphocyte infiltration by lymphocyte specific protein tyrosine kinase (LCK) marker expression. Based on these results, we propose targeting MAGE-A3 in UPS/MFS by immunotherapy techniques.
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http://dx.doi.org/10.3390/cancers11050677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562561PMC
May 2019

CXCR5CD8 T cells are a distinct functional subset with an antitumor activity.

Leukemia 2019 11 25;33(11):2640-2653. Epub 2019 Apr 25.

Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.

CXCR5 mediates homing of both B and follicular helper T (T) cells into follicles of secondary lymphoid organs. We found that CXCR5CD8 T cells are present in human tonsils and follicular lymphoma, inhibit T-mediated B cell differentiation, and exhibit strong cytotoxic activity. Consistent with these findings, adoptive transfer of CXCR5CD8 T cells into an animal model of lymphoma resulted in significantly greater antitumor activity than CXCR5CD8 T cells. Furthermore, RNA-Seq-based transcriptional profiling revealed 77 differentially expressed genes unique to CXCR5CD8 T cells. Among these, a signature comprised of 33 upregulated genes correlated with improved survival in follicular lymphoma patients. We also showed that CXCR5CD8 T cells could be induced and expanded ex vivo using IL-23 plus TGF-β, suggesting a possible strategy to generate these cells for clinical application. In summary, our study identified CXCR5CD8 T cells as a distinct T cell subset with ability to suppress T-mediated B cell differentiation, exert strong antitumor activity, and confer favorable prognosis in follicular lymphoma patients.
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http://dx.doi.org/10.1038/s41375-019-0464-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814517PMC
November 2019

Defective Localization With Impaired Tumor Cytotoxicity Contributes to the Immune Escape of NK Cells in Pancreatic Cancer Patients.

Front Immunol 2019 9;10:496. Epub 2019 Apr 9.

Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, South Korea.

Tumor-infiltrating lymphocytes (TILs), found in patients with advanced pancreatic ductal adenocarcinoma (PDAC), are shown to correlate with overall survival (OS) rate. Although majority of TILs consist of CD8/CD4 T cells, the presence of NK cells and their role in the pathogenesis of PDAC remains elusive. We performed comprehensive analyses of TIL, PBMC, and autologous tumor cells from 80 enrolled resectable PDAC patients to comprehend the NK cell defects within PDAC. Extremely low frequencies of NK cells (<0.5%) were found within PDAC tumors, which was attributable not to the low expression of tumor chemokines, but to the lack of chemokine receptor, CXCR2. Forced expression of CXCR2 in patients' NK cells rendered them capable of trafficking into PDAC. Furthermore, NK cells exhibited impaired cell-mediated killing of autologous PDAC cells, primarily due to insufficient ligation of NKG2D and DNAM-1, and failed to proliferate within the hypoxic tumor microenvironment. Importantly, these defects could be overcome by stimulation of NK cells from such patients. Importantly, when the proliferative capacity of NK cells was used to stratify patients on the basis of cell expansion, patients whose NK cells proliferated <250-fold experienced significantly lower DFS and OS than those with ≥250-fold. activation of NK cells restored tumor trafficking and reactivity, hence provided a therapeutic modality while their fold expansion could be a potentially significant prognostic indicator of OS and DFS in such patients.
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http://dx.doi.org/10.3389/fimmu.2019.00496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465515PMC
August 2020

Hydrodynamic shear stress promotes epithelial-mesenchymal transition by downregulating ERK and GSK3β activities.

Breast Cancer Res 2019 01 16;21(1). Epub 2019 Jan 16.

Department of Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea.

Background: Epithelial-mesenchymal transition (EMT) occurs in the tumor microenvironment and presents an important mechanism of tumor cell intravasation, stemness acquisition, and metastasis. During metastasis, tumor cells enter the circulation to gain access to distant tissues, but how this fluid microenvironment influences cancer cell biology is poorly understood.

Methods And Results: Here, we present both in vivo and in vitro evidence that EMT-like transition also occurs in circulating tumor cells (CTCs) as a result of hydrodynamic shear stress (+SS), which promotes conversion of CD24/CD44/CD133/CXCR4/ALDH1 primary patient epithelial tumor cells into specific high sphere-forming CD24/CD44/CD133/CXCR4/ALDH1 cancer stem-like cells (CSLCs) or tumor-initiating cells (TICs) with elevated tumor progression and metastasis capacity in vitro and in vivo. We demonstrate that conversion of CSLCs/TICs from epithelial tumor cells via +SS is dependent on reactive oxygen species (ROS)/nitric oxide (NO) generation, and suppression of extracellular signal-related kinase (ERK)/glycogen synthase kinase (GSK)3β, a mechanism similar to that operating in embryonic stem cells to prevent their differentiation while promoting self-renewal.

Conclusion: Fluid shear stress experienced during systemic circulation of human breast tumor cells can lead to specific acquisition of mesenchymal stem cell (MSC)-like potential that promotes EMT, mesenchymal-epithelial transition, and metastasis to distant organs. Our data revealed that biomechanical forces appeared to be important microenvironmental factors that not only drive hematopoietic development but also lead to acquisition of CSLCs/TIC potential in cancer metastasis. Our data highlight that +SS is a critical factor that promotes the conversion of CTCs into distinct TICs in blood circulation by endowing plasticity to these cells and by maintaining their self-renewal signaling pathways.
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http://dx.doi.org/10.1186/s13058-018-1071-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335853PMC
January 2019

Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer.

Proc Natl Acad Sci U S A 2019 01 11;116(5):1692-1697. Epub 2019 Jan 11.

The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77054;

Immune checkpoint therapy (ICT) has transformed cancer treatment in recent years; however, treatment response is not uniform across tumor types. The tumor immune microenvironment plays a critical role in determining response to ICT; therefore, understanding the differential immune infiltration between ICT-sensitive and ICT-resistant tumor types will help to develop effective treatment strategies. We performed a comprehensive analysis of the immune tumor microenvironment of an ICT-sensitive tumor (melanoma, = 44) and an ICT-resistant tumor (pancreatic cancer, = 67). We found that a pancreatic tumor has minimal to moderate infiltration of CD3, CD4, and CD8 T cells; however, the immune infiltrates are predominantly present in the stromal area of the tumor and are excluded from tumoral area compared with melanoma, where the immune infiltrates are primarily present in the tumoral area. Metastatic pancreatic ductal adenocarcinomas (PDACs) had a lower infiltration of total T cells compared with resectable primary PDACs, suggesting that metastatic PDACs have poor immunogenicity. Further, a significantly higher number of CD68 macrophages and VISTA cells (also known as V-domain immunoglobulin suppressor of T cell activation) were found in the pancreatic stromal area compared with melanoma. We identified VISTA as a potent inhibitory checkpoint that is predominantly expressed on CD68+ macrophages on PDACs. These data suggest that VISTA may be a relevant immunotherapy target for effective treatment of patients with pancreatic cancer.
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http://dx.doi.org/10.1073/pnas.1811067116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358697PMC
January 2019

Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience.

J Immunother Cancer 2019 01 6;7(1). Epub 2019 Jan 6.

Division of Internal Medicine, Section of Nephrology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1468, Houston, TX, 77030, USA.

Rationale & Objective: The approved therapeutic indication for immune checkpoint inhibitors (CPIs) are rapidly expanding including treatment in the adjuvant setting, the immune related toxicities associated with CPI can limit the efficacy of these agents. The literature on the nephrotoxicity of CPI is limited. Here, we present cases of biopsy proven acute tubulointerstitial nephritis (ATIN) and glomerulonephritis (GN) induced by CPIs and discuss potential mechanisms of these adverse effects.

Study Design, Setting, & Participants: We retrospectively reviewed all cancer patients from 2008 to 2018 who were treated with a CPI and subsequently underwent a kidney biopsy at The University of Texas MD Anderson Cancer Center.

Results: We identified 16 cases diagnosed with advanced solid or hematologic malignancy; 12 patients were male, and the median age was 64 (range 38 to 77 years). The median time to developing acute kidney injury (AKI) from starting CPIs was 14 weeks (range 6-56 weeks). The average time from AKI diagnosis to obtaining renal biopsy was 16 days (range from 1 to 46 days). Fifteen cases occurred post anti-PD-1based therapy. ATIN was the most common pathologic finding on biopsy (14 of 16) and presented in almost all cases as either the major microscopic finding or as a mild form of interstitial inflammation in association with other glomerular pathologies (pauci-immune glomerulonephritis, membranous glomerulonephritis, C3 glomerulonephritis, immunoglobulin A (IgA) nephropathy, or amyloid A (AA) amyloidosis). CPIs were discontinued in 15 out of 16 cases. Steroids and further immunosuppression were used in most cases as indicated for treatment of ATIN and glomerulonephritis (14 of 16), with the majority achieving complete to partial renal recovery.

Conclusions: Our data demonstrate that CPI related AKI occurs relatively late after CPI therapy. Our biopsy data demonstrate that ATIN is the most common pathological finding; however it can frequently co-occur with other glomerular pathologies, which may require immune suppressive therapy beyond corticosteroids. In the lack of predictive blood or urine biomarker, we recommend obtaining kidney biopsy for CPI related AKI.
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http://dx.doi.org/10.1186/s40425-018-0478-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322290PMC
January 2019

Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis.

J Immunother Cancer 2018 10 11;6(1):103. Epub 2018 Oct 11.

Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Immune-related enterocolitis (irEC) is the most common serious complication from checkpoint inhibitors (CPIs). The current front-line treatment for irEC, high-dose corticosteroids (CS), have significant side effects and prolonged therapy may reduce CPI-anti-tumor activity. Early addition of TNF-α inhibitors such as infliximab (IFX) may expedite symptom resolution and shorten CS duration. Thus, we conducted the first retrospective study, to our knowledge, evaluating symptom resolution in patients with irEC treated with and without IFX.

Methods: Data were collected from the medical records of patients diagnosed with irEC. The primary endpoint was time to symptom resolution for irEC for cases managed with IFX plus CS (IFX group) versus CS alone (CS group). Duration of CS, overall survival (OS), and time to treatment failure (TTF) were secondary endpoints.

Results: Among 75 patients with irEC, 52% received CS alone, and 48% received IFX. Despite higher grade colitis in the IFX group (grade 3/4: 86% vs. 34%; p < 0.001), median times to diarrhea resolution (3 vs. 9 days; p < 0.001) and to steroid titration (4 vs. 13 days; p < 0.001) were shorter in the IFX group than in the CS group without a negative impact on TTF or OS. Total steroid duration (median 35 vs. 51 days; p = 0.150) was numerically lower in the IFX group.

Conclusions: Despite higher incidence of grade 3/4 colitis, IFX added to CS for the treatment of patients with irEC was associated with a significantly shorter time to symptom resolution. The data suggest that early introduction of IFX should be considered for patients with irEC until definitive prospective clinical trials are conducted.
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http://dx.doi.org/10.1186/s40425-018-0412-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180568PMC
October 2018