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Article ; Online: Targeting Ovarian Cancer with IL-2 Cytokine/Antibody Complexes: A Summary and Recent Advances.

Deng, Yilun / Reyes, Ryan M / Zhang, Chenghao / Conejo-Garcia, José / Curiel, Tyler J

Journal of cellular immunology

2022 Volume 3, Issue 6, Page(s) 387–396

Language	English
Publishing date	2022-10-17
Publishing country	United States
Document type	Journal Article
ISSN	2689-2812
ISSN (online)	2689-2812
DOI	10.33696/immunology.3.122
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: A Randomized Feasibility Trial Comparing Surveillance Regimens for Patients with Low and Low-Intermediate Risk Non-Muscle Invasive Bladder Cancer.

Reyes, Ryan M / Rios, Emily / Barney, Shane / Hugen, Cory M / Michalek, Joel E / Lotan, Yair / Messing, Edward M / Svatek, Robert S

Bladder cancer (Amsterdam, Netherlands)

2021 Volume 7, Issue 3, Page(s) 285–295

Abstract: Background: Surveillance regimens for non-muscle invasive bladder cancer (NMIBC) are disparate and controlled trials could inform guidelines. The feasibility of randomizing patients to variable frequency surveillance is unknown.: Objectives: To ... ...

Abstract	Background: Surveillance regimens for non-muscle invasive bladder cancer (NMIBC) are disparate and controlled trials could inform guidelines. The feasibility of randomizing patients to variable frequency surveillance is unknown. Objectives: To determine patient willingness to randomization to high frequency (HF) versus low frequency (LF) surveillance regimen for NMIBC and compare patient comfort and healthcare costs across regimens. Methods: A non-blinded, two-arm, randomized-controlled study of patients with low or low-intermediate risk NMIBC was conducted at two institutions where patients were offered randomization to HF vs. LF surveillance following initial tumor resection. The HF group underwent cystoscopy every three months for 2 years, then every 6 months for 2 years, then annually. The LF group underwent cystoscopy at 9 months following the 3-month cystoscopy, then annually. Assuming 75% of patients approached would agree to enrollment, a sample size of Results: Of 70 patients approached, 45 (64.3%) agreed to participate and 25 (35.7%) declined enrollment due to preference for HF. Twelve biopsies were performed, including 4 (19%) of 21 patients in the HF group and 8 (33.3%) of 24 patients in the LF group. Disease recurrence (low grade Ta) was observed in 3 (14.3%) and 5 (20.8%) patients in the HF and LF groups, respectively. No patients experienced high grade recurrence or progression. Both groups had similar patient-reported procedure-related discomfort and quality of life measures over time. Patient out-of-pocket cost and healthcare systems costs were $383.80 more per patient annually in the HF group. Conclusions: Randomization to variable frequency surveillance is challenging as over a third of patients declined participation. However, these data provide important preliminary insights into the potential effects of surveillance frequency on oncologic and economic outcomes in patients with low and low-intermediate risk bladder cancer.
Language	English
Publishing date	2021-09-21
Publishing country	Netherlands
Document type	Journal Article
ISSN	2352-3727
ISSN	2352-3727
DOI	10.3233/blc-201535
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Article ; Online: Immune checkpoint expression and relationships to anti-PD-L1 immune checkpoint blockade cancer immunotherapy efficacy in aged versus young mice.

Garcia, Myrna G / Deng, Yilun / Murray, Clare / Reyes, Ryan M / Padron, Alvaro / Bai, Haiyan / Kancharla, Aravind / Gupta, Harshita / Shen-Orr, Shai / Curiel, Tyler J

Aging and cancer

2022 Volume 3, Issue 1, Page(s) 68–83

Abstract: Introduction: Aging is the biggest cancer risk, and immune checkpoint (IC) inhibition (ICI) is a revolutionary cancer immunotherapy approach. Nonetheless, there are limited preclinical/clinical data regarding aging effects on ICI outcomes or age effects ...

Abstract	Introduction: Aging is the biggest cancer risk, and immune checkpoint (IC) inhibition (ICI) is a revolutionary cancer immunotherapy approach. Nonetheless, there are limited preclinical/clinical data regarding aging effects on ICI outcomes or age effects on IC expression in different organs or tumors. Methods: Flow cytometry assessed IC on immune and non-immune cells in various organs in young and aged BL6 mice. Comparisons: aged versus young naïve WT versus interferon- Results: α Conclusion: Age affects IC expression on specific immune cells in an organ- and tissue-specific manner. ICs were generally higher on aged immune cells. High immune-cell PD-1 could help explain
Language	English
Publishing date	2022-02-25
Publishing country	United States
Document type	Journal Article
ISSN	2643-8909
ISSN (online)	2643-8909
DOI	10.1002/aac2.12045
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Article ; Online: CD122-targeted interleukin-2 and αPD-L1 treat bladder cancer and melanoma via distinct mechanisms, including CD122-driven natural killer cell maturation.

Reyes, Ryan M / Zhang, Chenghao / Deng, Yilun / Ji, Niannian / Mukherjee, Neelam / Padron, Alvaro S / Clark, Curtis A / Svatek, Robert S / Curiel, Tyler J

Oncoimmunology

2021 Volume 10, Issue 1, Page(s) 2006529

Abstract: Bladder cancer (BC) and melanoma are amenable to immune checkpoint blockade (ICB) therapy, yet most patients with advanced/metastatic disease do not respond. CD122-targeted interleukin (IL)-2 can improve ICB efficacy, but mechanisms are unclear. We ... ...

Abstract	Bladder cancer (BC) and melanoma are amenable to immune checkpoint blockade (ICB) therapy, yet most patients with advanced/metastatic disease do not respond. CD122-targeted interleukin (IL)-2 can improve ICB efficacy, but mechanisms are unclear. We tested αPD-L1 and CD122-directed immunotherapy with IL-2/αIL-2 complexes (IL-2c) in primary and metastatic bladder and melanoma tumors. IL-2c treatment of orthotopic MB49 and MBT-2 BC generated NK cell antitumor immunity through enhanced activation, reduced exhaustion, and promotion of a mature, effector NK cell phenotype. By comparison, subcutaneous B16-F10 melanoma, which is IL-2c sensitive, requires CD8
MeSH term(s)	Animals ; B7-H1 Antigen/genetics ; Humans ; Interleukin-2 ; Killer Cells, Natural ; Melanoma, Experimental/drug therapy ; Mice ; Tumor Microenvironment ; Urinary Bladder Neoplasms/drug therapy
Chemical Substances	B7-H1 Antigen ; Interleukin-2
Language	English
Publishing date	2021-11-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2645309-5
ISSN	2162-402X ; 2162-4011
ISSN (online)	2162-402X
ISSN	2162-4011
DOI	10.1080/2162402X.2021.2006529
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Article ; Online: Rapamycin enhances BCG-specific γδ T cells during intravesical BCG therapy for non-muscle invasive bladder cancer: a randomized, double-blind study.

Ji, Niannian / Mukherjee, Neelam / Reyes, Ryan M / Gelfond, Jonathan / Javors, Martin / Meeks, Joshua J / McConkey, David J / Shu, Zhen-Ju / Ramamurthy, Chethan / Dennett, Ryan / Curiel, Tyler J / Svatek, Robert S

Journal for immunotherapy of cancer

2021 Volume 9, Issue 3

Abstract: Background: Although intravesical BCG is the standard treatment of high-grade non-muscle invasive bladder cancer (NMIBC), response rates remain unsatisfactory. In preclinical models, rapamycin enhances BCG vaccine efficacy against tuberculosis and the ... ...

Abstract	Background: Although intravesical BCG is the standard treatment of high-grade non-muscle invasive bladder cancer (NMIBC), response rates remain unsatisfactory. In preclinical models, rapamycin enhances BCG vaccine efficacy against tuberculosis and the killing capacity of γδ T cells, which are critical for BCG's antitumor effects. Here, we monitored immunity, safety, and tolerability of rapamycin combined with BCG in patients with NMIBC. Methods: A randomized double-blind trial of oral rapamycin (0.5 or 2.0 mg daily) versus placebo for 1 month was conducted in patients with NMIBC concurrently receiving 3 weekly BCG instillations (NCT02753309). The primary outcome was induction of BCG-specific γδ T cells, measured as a percentage change from baseline. Post-BCG urinary cytokines and immune cells were examined as surrogates for local immune response in the bladder. Secondary outcomes measured were adverse events (AEs) and tolerability using validated patient-reported questionnaires. Results: Thirty-one patients were randomized (11 placebo, 8 rapamycin 2.0 mg, and 12 rapamycin 0.5 mg). AEs were similar across groups and most were grade 1-2. One (12.5%) patient randomized to 2.0 mg rapamycin was taken off treatment due to stomatitis. No significant differences in urinary symptoms, bowel function, or bother were observed between groups. The median (IQR) percentage change in BCG-specific γδ T cells from baseline per group was as follows: -26% (-51% to 24%) for placebo, 9.6% (-59% to 117%) for rapamycin 0.5 mg (versus placebo, p=0.18), and 78.8% (-31% to 115%) for rapamycin 2.0 mg (versus placebo, p=0.03). BCG-induced cytokines showed a progressive increase in IL-8 (p=0.02) and TNF-α (p=0.04) over time for patients on rapamycin 2.0 mg, whereas patients receiving placebo had no significant change in urinary cytokines. Compared with placebo, patients receiving 2.0 mg rapamycin had increased urinary γδ T cells at the first week of BCG (p=0.02). Conclusions: Four weeks of 0.5 and 2.0 mg oral rapamycin daily is safe and tolerable in combination with BCG for patients with NMIBC. Rapamycin enhances BCG-specific γδ T cell immunity and boosts urinary cytokines during BCG treatment. Further study is needed to determine long-term rapamycin safety, tolerability and effects on BCG efficacy.
MeSH term(s)	Adjuvants, Immunologic/administration & dosage ; Adjuvants, Immunologic/adverse effects ; Administration, Intravesical ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; BCG Vaccine/administration & dosage ; BCG Vaccine/adverse effects ; Cytokines/urine ; Double-Blind Method ; Female ; Humans ; Intraepithelial Lymphocytes/drug effects ; Intraepithelial Lymphocytes/immunology ; Intraepithelial Lymphocytes/metabolism ; Male ; Middle Aged ; Neoplasm Grading ; Neoplasm Invasiveness ; Neoplasm Staging ; Phenotype ; Sirolimus/administration & dosage ; Sirolimus/adverse effects ; Time Factors ; Treatment Outcome ; Tumor Microenvironment ; Urinary Bladder Neoplasms/drug therapy ; Urinary Bladder Neoplasms/immunology ; Urinary Bladder Neoplasms/pathology ; Urinary Bladder Neoplasms/urine ; Urine/chemistry ; Urine/cytology
Chemical Substances	Adjuvants, Immunologic ; BCG Vaccine ; Cytokines ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2021-03-03
Publishing country	England
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2020-001941
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Article ; Online: γδ T Cells Support Antigen-Specific αβ T cell-Mediated Antitumor Responses during BCG Treatment for Bladder Cancer.

Ji, Niannian / Mukherjee, Neelam / Shu, Zhen-Ju / Reyes, Ryan M / Meeks, Joshua J / McConkey, David J / Gelfond, Jonathan A / Curiel, Tyler J / Svatek, Robert S

Cancer immunology research

2021 Volume 9, Issue 12, Page(s) 1491–1503

Abstract: Bacillus Calmette-Guérin (BCG) is the most effective intravesical agent at reducing recurrence for patients with high-grade, non-muscle-invasive bladder cancer. Nevertheless, response to BCG is variable and strategies to boost BCG efficacy have not ... ...

Abstract	Bacillus Calmette-Guérin (BCG) is the most effective intravesical agent at reducing recurrence for patients with high-grade, non-muscle-invasive bladder cancer. Nevertheless, response to BCG is variable and strategies to boost BCG efficacy have not materialized. Prior work demonstrated a requirement for either conventional αβ or nonconventional γδ T cells in mediating BCG treatment efficacy, yet the importance of T-cell antigen specificity for BCG's treatment effect is unclear. Here, we provide direct evidence to show that BCG increases the number of tumor antigen-specific αβ T cells in patients with bladder cancer and protects mice from subsequent same-tumor challenge, supporting BCG induction of tumor-specific memory and protection. Adoptive T-cell transfers of antigen-specific αβ T cells into immunodeficient mice challenged with syngeneic MB49 bladder tumors showed that both tumor and BCG antigen-specific αβ T cells contributed to BCG efficacy. BCG-specific antitumor immunity, however, also required nonconventional γδ T cells. Prior work shows that the mTOR inhibitor rapamycin induces the proliferation and effector function of γδ T cells. Here, rapamycin increased BCG efficacy against both mouse and human bladder cancer
MeSH term(s)	Animals ; BCG Vaccine/pharmacology ; BCG Vaccine/therapeutic use ; Cell Line, Tumor ; Disease Models, Animal ; Female ; Humans ; Immunotherapy/methods ; Intraepithelial Lymphocytes/immunology ; Male ; Mice ; T-Lymphocytes/metabolism ; Urinary Bladder Neoplasms/drug therapy
Chemical Substances	BCG Vaccine
Language	English
Publishing date	2021-10-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-21-0285
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Zs.A 7022: Show issues

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Article ; Online: Bladder cancer cell-intrinsic PD-L1 signals promote mTOR and autophagy activation that can be inhibited to improve cytotoxic chemotherapy.

Zhang, Deyi / Reyes, Ryan M / Osta, Erica / Kari, Suresh / Gupta, Harshita B / Padron, Alvaro S / Kornepati, Anand V R / Kancharla, Aravind / Sun, Xiujie / Deng, Yilun / Wu, Bogang / Vadlamudi, Ratna / Li, Rong / Svatek, Robert S / Curiel, Tyler J

Cancer medicine

2021 Volume 10, Issue 6, Page(s) 2137–2152

Abstract: Tumor cell-intrinsic programmed death-ligand 1 (PD-L1) signals mediate immunopathologic effects in breast, colon, and ovarian cancers and in melanomas, but bladder cancer (BC) effects are unreported. We show here that BC cell-intrinsic PD-L1 signals in ... ...

Abstract	Tumor cell-intrinsic programmed death-ligand 1 (PD-L1) signals mediate immunopathologic effects in breast, colon, and ovarian cancers and in melanomas, but bladder cancer (BC) effects are unreported. We show here that BC cell-intrinsic PD-L1 signals in mouse MB49 and human RT4, UM-UC3, and UM-UC-14 BC cells regulate important pathologic pathways and processes, including effects not reported in other cancers. α-PD-L1 antibodies reduced BC cell proliferation in vitro, demonstrating direct signaling effects. BC cell-intrinsic PD-L1 promoted mammalian target of rapamycin complex 1 (mTORC1) signals in vitro and augmented in vivo immune-independent cell growth and metastatic cancer spread, similar to effects we reported in melanoma and ovarian cancer. BC cell-intrinsic PD-L1 signals also promoted basal and stress-induced autophagy, whereas these signals inhibited autophagy in melanoma and ovarian cancer cells. BC cell-intrinsic PD-L1 also mediated chemotherapy resistance to the commonly used BC chemotherapy agents cis-platinum and gemcitabine and to the mTORC1 inhibitor, rapamycin. Thus, BC cell-intrinsic PD-L1 signals regulate important virulence and treatment resistance pathways that suggest novel, actionable treatment targets meriting additional studies. As a proof-of-concept, we showed that the autophagy inhibitor chloroquine improved cis-platinum treatment efficacy in vivo, with greater efficacy in PD-L1 null versus PD-L1-replete BC.
MeSH term(s)	Animals ; Antibiotics, Antineoplastic/therapeutic use ; Autophagy/drug effects ; Autophagy/physiology ; B7-H1 Antigen/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Chloroquine/pharmacology ; Cisplatin/therapeutic use ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/therapeutic use ; Drug Resistance, Neoplasm ; Female ; Gene Expression ; Humans ; Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Melanoma/metabolism ; Melanoma/physiopathology ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Mice, SCID ; Neoplasm Metastasis ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/physiopathology ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; Sirolimus/therapeutic use ; Urinary Bladder Neoplasms/drug therapy ; Urinary Bladder Neoplasms/genetics ; Urinary Bladder Neoplasms/immunology ; Urinary Bladder Neoplasms/metabolism ; Gemcitabine
Chemical Substances	Antibiotics, Antineoplastic ; B7-H1 Antigen ; CD274 protein, human ; Deoxycytidine (0W860991D6) ; Chloroquine (886U3H6UFF) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Cisplatin (Q20Q21Q62J) ; Sirolimus (W36ZG6FT64) ; Gemcitabine
Language	English
Publishing date	2021-02-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2659751-2
ISSN	2045-7634 ; 2045-7634
ISSN (online)	2045-7634
ISSN	2045-7634
DOI	10.1002/cam4.3739
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Article ; Online: Urinary Diversion Disparity Following Radical Cystectomy for Bladder Cancer in the Hispanic Population.

Rios, Emily M / Parma, Mitchell A / Fernandez, Roman A / Clinton, Timothy N / Reyes, Ryan M / Kaushik, Dharam / Pruthi, Deepak / Mansour, Ahmed M / Mukherjee, Neelam / Gelfond, Jon / Wheeler, Karen M / Svatek, Robert S

Urology

2019 Volume 137, Page(s) 66–71

Abstract: Objective: To determine if disparities in quality of surgical care exist between Hispanics and non-Hispanics undergoing radical cystectomy for bladder cancer.: Materials and methods: An observational cohort study was conducted retrospectively on ... ...

Abstract	Objective: To determine if disparities in quality of surgical care exist between Hispanics and non-Hispanics undergoing radical cystectomy for bladder cancer. Materials and methods: An observational cohort study was conducted retrospectively on patients who underwent radical cystectomy for urothelial carcinoma of the bladder at our institution between January 2005 and July 2018. Data was collected on demographic, clinical, and pathological characteristics of patients, including self-reported ethnicity. Univariable and multivariable logistic or linear regression analyses were used to evaluate the association of ethnicity with receipt of neoadjuvant chemotherapy, utilization of laparoscopic surgery, number of lymph nodes removed, and continent urinary diversion. Results: We identified 507 patients in our database out of which, 136 (27%) were Hispanic and 371 (73%) were non-Hispanic. Compared to non-Hispanics, Hispanics had a higher body mass index (26.9 kg/m Conclusion: Disparity exists in the delivery of continent urinary diversions for Hispanic patients undergoing radical cystectomy for bladder cancer. Further investigation is needed to determine the potential causes for this disparity in care delivered.
MeSH term(s)	Aged ; Cohort Studies ; Cystectomy/methods ; Female ; Healthcare Disparities/statistics & numerical data ; Hispanic or Latino/statistics & numerical data ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Urinary Bladder Neoplasms/surgery ; Urinary Diversion/statistics & numerical data
Language	English
Publishing date	2019-12-27
Publishing country	United States
Document type	Journal Article ; Observational Study
ZDB-ID	192062-5
ISSN	1527-9995 ; 0090-4295
ISSN (online)	1527-9995
ISSN	0090-4295
DOI	10.1016/j.urology.2019.12.017
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Zs.A 1142: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 275: Show issues

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Article ; Online: CD122-Selective IL2 Complexes Reduce Immunosuppression, Promote Treg Fragility, and Sensitize Tumor Response to PD-L1 Blockade.

Drerup, Justin M / Deng, Yilun / Pandeswara, Sri Lakshmi / Padrón, Álvaro S / Reyes, Ryan M / Zhang, Xinyue / Mendez, Jenny / Liu, Aijie / Clark, Curtis A / Chen, Wanjiao / Conejo-Garcia, José R / Hurez, Vincent / Gupta, Harshita / Curiel, Tyler J

Cancer research

2020 Volume 80, Issue 22, Page(s) 5063–5075

Abstract: The IL2 receptor (IL2R) is an attractive cancer immunotherapy target that controls immunosuppressive T regulatory cells (Treg) and antitumor T cells. Here we used IL2Rβ-selective IL2/anti-IL2 complexes (IL2c) to stimulate effector T cells preferentially ... ...

Abstract	The IL2 receptor (IL2R) is an attractive cancer immunotherapy target that controls immunosuppressive T regulatory cells (Treg) and antitumor T cells. Here we used IL2Rβ-selective IL2/anti-IL2 complexes (IL2c) to stimulate effector T cells preferentially in the orthotopic mouse ID8agg ovarian cancer model. Despite strong tumor rejection, IL2c unexpectedly lowered the tumor microenvironmental CD8
MeSH term(s)	Animals ; Ascites/immunology ; B7-H1 Antigen/antagonists & inhibitors ; CD8-Positive T-Lymphocytes/cytology ; CD8-Positive T-Lymphocytes/immunology ; Female ; Immune Tolerance ; Immunity, Cellular ; Immunologic Memory ; Immunotherapy/methods ; Interleukin-2/pharmacology ; Interleukin-2 Receptor beta Subunit/antagonists & inhibitors ; Interleukin-2 Receptor beta Subunit/immunology ; Melanoma, Experimental/immunology ; Melanoma, Experimental/therapy ; Mice ; Mice, Inbred C57BL ; Ovarian Neoplasms/immunology ; Ovarian Neoplasms/therapy ; Phenotype ; Random Allocation ; Receptors, Interleukin-2/metabolism ; T-Lymphocyte Subsets/metabolism ; T-Lymphocytes, Regulatory/cytology ; T-Lymphocytes, Regulatory/immunology ; Tumor Microenvironment/immunology
Chemical Substances	B7-H1 Antigen ; IL2RB protein, human ; Interleukin-2 ; Interleukin-2 Receptor beta Subunit ; Receptors, Interleukin-2
Language	English
Publishing date	2020-09-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-20-0002
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