Publications by authors named "Holbrook E Kohrt"

73 Publications

Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sézary Syndrome: A Multicenter Phase II Study.

J Clin Oncol 2020 01 18;38(1):20-28. Epub 2019 Sep 18.

Stanford University, Stanford, CA.

Purpose: To assess the efficacy of pembrolizumab in patients with advanced relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS).

Patients And Methods: CITN-10 is a single-arm, multicenter phase II trial of 24 patients with advanced MF or SS. Patients were treated with pembrolizumab 2 mg/kg every 3 weeks for up to 24 months. The primary end point was overall response rate by consensus global response criteria.

Results: Patients had advanced-stage disease (23 of 24 with stage IIB to IV MF/SS) and were heavily pretreated with a median of four prior systemic therapies. The overall response rate was 38% with two complete responses and seven partial responses. Of the nine responding patients, six had 90% or more improvement in skin disease by modified Severity Weighted Assessment Tool, and eight had ongoing responses at last follow-up. The median duration of response was not reached, with a median response follow-up time of 58 weeks. Immune-related adverse events led to treatment discontinuation in four patients. A transient worsening of erythroderma and pruritus occurred in 53% of patients with SS. This cutaneous flare reaction did not result in treatment discontinuation for any patient. The flare reaction correlated with high PD-1 expression on Sézary cells but did not associate with subsequent clinical responses or lack of response. Treatment responses did not correlate with expression of PD-L1, total mutation burden, or an interferon-γ gene expression signature.

Conclusion: Pembrolizumab demonstrated significant antitumor activity with durable responses and a favorable safety profile in patients with advanced MF/SS.
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http://dx.doi.org/10.1200/JCO.19.01056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943974PMC
January 2020

A First-in-Human Phase I Study of Subcutaneous Outpatient Recombinant Human IL15 (rhIL15) in Adults with Advanced Solid Tumors.

Clin Cancer Res 2018 04 4;24(7):1525-1535. Epub 2017 Dec 4.

Fred Hutchinson Cancer Research Center, Seattle, Washington.

Preclinical data established IL15 as a homeostatic factor and powerful stimulator of NK and CD8 T-cell function, the basis for clinical testing. A first-in-human outpatient phase I dose escalation trial of subcutaneous (SC) rhIL15 was conducted in refractory solid tumor cancer patients. Therapy consisted of daily (Monday-Friday) subcutaneous injections of rhIL15 for two consecutive weeks (10 total doses/cycle). Clinical response was assessed by RECIST. Pharmacokinetics of rhIL15 and immune biomarkers were evaluated. Nineteen patients were treated with rhIL15 at dose levels of 0.25, 0.5, 1, 2, and 3 mcg/kg/day. Fourteen patients completed ≥ 2 cycles of therapy that was well tolerated. One serious adverse event (SAE), grade 2 pancreatitis, required overnight hospitalization. Enrollment was halted after a patient receiving 3 mcg/kg/day developed a dose-limiting SAE of grade 3 cardiac chest pain associated with hypotension and increased troponin. No objective responses were observed; however, several patients had disease stabilization including a renal cell carcinoma patient who continued protocol treatment for 2 years. The treatment induced profound expansion of circulating NK cells, especially among the CD56 subset. A proportional but less dramatic increase was found among circulating CD8 T cells with maximal 3-fold expansion for the 2 and 3 mcg/kg patients. SC rhIL15 treatment was well tolerated, producing substantial increases in circulating NK and CD8 T cells. This protocol establishes a safe outpatient SC rhIL15 regimen of 2 mcg/kg/day dosing amenable to self-injection and with potential as a combination immunotherapeutic agent. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6741437PMC
April 2018

Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens.

Nature 2017 03 22;543(7647):723-727. Epub 2017 Mar 22.

Department of Medicine, Division of Oncology, Stanford University, Stanford, California 94305, USA.

Cancer somatic mutations can generate neoantigens that distinguish malignant from normal cells. However, the personalized identification and validation of neoantigens remains a major challenge. Here we discover neoantigens in human mantle-cell lymphomas by using an integrated genomic and proteomic strategy that interrogates tumour antigen peptides presented by major histocompatibility complex (MHC) class I and class II molecules. We applied this approach to systematically characterize MHC ligands from 17 patients. Remarkably, all discovered neoantigenic peptides were exclusively derived from the lymphoma immunoglobulin heavy- or light-chain variable regions. Although we identified MHC presentation of private polymorphic germline alleles, no mutated peptides were recovered from non-immunoglobulin somatically mutated genes. Somatic mutations within the immunoglobulin variable region were almost exclusively presented by MHC class II. We isolated circulating CD4 T cells specific for immunoglobulin-derived neoantigens and found these cells could mediate killing of autologous lymphoma cells. These results demonstrate that an integrative approach combining MHC isolation, peptide identification, and exome sequencing is an effective platform to uncover tumour neoantigens. Application of this strategy to human lymphoma implicates immunoglobulin neoantigens as targets for lymphoma immunotherapy.
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http://dx.doi.org/10.1038/nature21433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808925PMC
March 2017

Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling.

Blood 2017 02 23;129(6):759-770. Epub 2016 Dec 23.

Oncology Division, Department of Medicine, Stanford University, Stanford, CA.

Kinases downstream of B-cell antigen receptor (BCR) represent attractive targets for therapy in non-Hodgkin lymphoma (NHL). As clinical responses vary, improved knowledge regarding activation and regulation of BCR signaling in individual patients is needed. Here, using phosphospecific flow cytometry to obtain malignant B-cell signaling profiles from 95 patients representing 4 types of NHL revealed a striking contrast between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) tumors. Lymphoma cells from diffuse large B-cell lymphoma patients had high basal phosphorylation levels of most measured signaling nodes, whereas follicular lymphoma cells represented the opposite pattern with no or very low basal levels. MCL showed large interpatient variability in basal levels, and elevated levels for the phosphorylated forms of AKT, extracellular signal-regulated kinase, p38, STAT1, and STAT5 were associated with poor outcome. CLL tumors had elevated basal levels for the phosphorylated forms of BCR-signaling nodes (Src family tyrosine kinase, spleen tyrosine kinase [SYK], phospholipase Cγ), but had low α-BCR-induced signaling. This contrasted MCL tumors, where α-BCR-induced signaling was variable, but significantly potentiated as compared with the other types. Overexpression of CD79B, combined with a gating strategy whereby signaling output was directly quantified per cell as a function of CD79B levels, confirmed a direct relationship between surface CD79B, immunoglobulin M (IgM), and IgM-induced signaling levels. Furthermore, α-BCR-induced signaling strength was variable across patient samples and correlated with BCR subunit CD79B expression, but was inversely correlated with susceptibility to Bruton tyrosine kinase (BTK) and SYK inhibitors in MCL. These individual differences in BCR levels and signaling might relate to differences in therapy responses to BCR-pathway inhibitors.
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http://dx.doi.org/10.1182/blood-2016-05-718494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5301824PMC
February 2017

Blood Stem Cell Activity Is Arrested by Th1-Mediated Injury Preventing Engraftment following Nonmyeloablative Conditioning.

J Immunol 2016 11 10;197(10):4151-4162. Epub 2016 Oct 10.

Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305;

T cells are widely used to promote engraftment of hematopoietic stem cells (HSCs) during an allogeneic hematopoietic cell transplantation. Their role in overcoming barriers to HSC engraftment is thought to be particularly critical when patients receive reduced doses of preparative chemotherapy and/or radiation compared with standard transplantations. In this study, we sought to delineate the effects CD4 cells on engraftment and blood formation in a model that simulates clinical hematopoietic cell transplantation by transplanting MHC-matched, minor histocompatibility-mismatched grafts composed of purified HSCs, HSCs plus bulk T cells, or HSCs plus T cell subsets into mice conditioned with low-dose irradiation. Grafts containing conventional CD4 T cells caused marrow inflammation and inhibited HSC engraftment and blood formation. Posttransplantation, the marrows of HSCs plus CD4 cell recipients contained IL-12-secreting CD11c cells and IFN-γ-expressing donor Th1 cells. In this setting, host HSCs arrested at the short-term stem cell stage and remained in the marrow in a quiescent cell cycling state (G). As a consequence, donor HSCs failed to engraft and hematopoiesis was suppressed. Our data show that Th1 cells included in a hematopoietic allograft can negatively impact HSC activity, blood reconstitution, and engraftment of donor HSCs. This potential negative effect of donor T cells is not considered in clinical transplantation in which bulk T cells are transplanted. Our findings shed new light on the effects of CD4 T cells on HSC biology and are applicable to other pathogenic states in which immune activation in the bone marrow occurs such as aplastic anemia and certain infectious conditions.
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http://dx.doi.org/10.4049/jimmunol.1500715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5096509PMC
November 2016

Anti-CD137 enhances anti-CD20 therapy of systemic B-cell lymphoma with altered immune homeostasis but negligible toxicity.

Oncoimmunology 2016 Jul 30;5(7):e1192740. Epub 2016 Jun 30.

Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; School of Medicine, University of Queensland, St Lucia, QLD, Australia.

Studies of sequential anti-CD137/anti-CD20 therapy have previously shown that the efficacy of anti-CD20 was heavily reliant upon anti-CD137; however, the exact mechanism of the anti-B-cell lymphoma efficacy, and whether this correlates with enhanced adverse effects or toxicity, had not been elucidated. Here, we observed that sequential anti-CD137 administration with anti-CD20 resulted in a synergistic therapy, largely dependent upon Fc receptors (FcR), to prolong survival in an experimental B-cell lymphoma therapy model. Tumor suppression was accompanied by B cell depletion, which was not dependent on one activating FcR. Surprisingly, the B-cell activating factor (BAFF) was elevated in the plasma of mice receiving anti-CD137 alone or in combination with anti-CD20, while a selective increase in some plasma cytokines was also noted and triggered by anti-CD137. These effects were independent of activating FcR. Sustained treatment of advanced lymphoma revealed increased lymphocyte infiltrates into the liver and a significant decrease in the metabolic capability of the liver in mice receiving anti-CD137. Importantly, these effects were not exacerbated in mice receiving the anti-CD20/CD137 combination, and elevations in classical liver damage markers such as alanine aminotransferase (ALT) were less than that caused by the lymphoma itself. Thus, combined anti-CD20/anti-CD137 treatment increases the therapeutic index of anti-CD20 or anti-CD137 alone. These mouse data were corroborated by ongoing clinical development studies to assess safety, tolerability and pharmacodynamic activity of human patients treated by this approach. Together, these data support the use of this sequential antibody therapeutic strategy to improve the efficacy of rituximab in B-cell lymphoma patients.
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http://dx.doi.org/10.1080/2162402X.2016.1192740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006917PMC
July 2016

Assessing Immune-Related Adverse Events of Efficacious Combination Immunotherapies in Preclinical Models of Cancer.

Cancer Res 2016 09 8;76(18):5288-301. Epub 2016 Aug 8.

Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia.

New combination immunotherapies are displaying both efficacy and immune-related adverse events (irAE) in humans. However, grade 3/4 irAEs occur in a high proportion, which can lead to discontinuation of treatment and can result in fatalities if not promptly treated. Prolonged T regulatory cell (Treg) depletion in tumor-bearing Foxp3-DTR mice using diphtheria toxin (DT) mirrored the spectrum of antitumor responses and severity of irAEs that can occur in ipilimumab/nivolumab-treated patients. In contrast, transient Treg depletion or anti-CTLA-4/PD-1 therapy had equivalent effects in mice, lowering the immune tolerance threshold and allowing irAEs to be more easily induced following treatment with additional immunomodulatory antibodies. Transient Treg depletion of DT in combination with anti-PD-1 or anti-TIM-3 monoclonal antibodies had a high therapeutic window compared with DT plus anti-CD137. In contrast, DT plus anti-CD137-treated mice developed severe irAEs similar to grade 3/4 clinical symptoms. These irAEs appeared because of an infiltration of activated proliferating effector T cells in the tissues producing IFNγ and TNF; however, TNF blockade decreased irAEs severity without impacting on tumor growth. Cancer Res; 76(18); 5288-301. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0194DOI Listing
September 2016

Strategic Combinations: The Future of Oncolytic Virotherapy with Reovirus.

Mol Cancer Ther 2016 05 14;15(5):767-73. Epub 2016 Apr 14.

Department of Medicine, Division of Oncology, Stanford University, Stanford, California.

The dominant cancer treatment modalities such as chemotherapy, radiotherapy, and even targeted kinase inhibitors and mAbs are limited by low efficacy, toxicity, and treatment-resistant tumor subclones. Oncolytic viral therapy offers a novel therapeutic strategy that has the potential to dramatically improve clinical outcomes. Reovirus, a double-stranded benign human RNA virus, is a leading candidate for therapeutic development and currently in phase III trials. Reovirus selectively targets transformed cells with activated Ras signaling pathways; Ras genes are some of the most frequently mutated oncogenes in human cancer and it is estimated that at least 30% of all human tumors exhibit aberrant Ras signaling. By targeting Ras-activated cells, reovirus can directly lyse cancer cells, disrupt tumor immunosuppressive mechanisms, reestablish multicellular immune surveillance, and generate robust antitumor responses. Reovirus therapy is currently being tested in combination with radiotherapy, chemotherapy, immunotherapy, and surgery. In this review, we discuss the current successes of these combinatorial therapeutic strategies and emphasize the importance of prioritizing combination oncolytic viral therapy as reovirus-based treatments progress in clinical development. Mol Cancer Ther; 15(5); 767-73. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-15-0695DOI Listing
May 2016

PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma.

N Engl J Med 2016 Jun 19;374(26):2542-52. Epub 2016 Apr 19.

From the University of Washington Medical Center (P.T.N., S. Bhatia, N.J.M., E.M.S., M.M.S., J.A.T., M.A.C.), Fred Hutchinson Cancer Research Center (P.T.N., S. Bhatia, S.P.F., L.L., J.A.T., M.A.C.), Cancer Immunotherapy Trials Network (S.P.F., L.L., M.A.C.), and Cancer Research and Biostatistics (A.M., L.R.S.) - all in Seattle; Johns Hopkins University School of Medicine and Kimmel Cancer Center, Baltimore (E.J.L., S. Berry, D.M.P., W.H.S., J.C.S., J.M.T., S.L.T.), and Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda. (E.S.) - both in Maryland; Winship Cancer Institute of Emory University, Atlanta (R.R.K.); Merck Research Laboratories, Kenilworth, NJ (L.A., E.K.C., S.M.T., J.H.Y.); University of California, San Francisco, San Francisco (A.D.), and Stanford University, Stanford (H.E.K., K.M., S.A.R.) - both in California; Mt. Sinai Medical Center, New York (P.A.F.); Yale University, New Haven, CT (H.M.K.); and Ohio State University, Columbus (T.O.).

Background: Merkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of interest, because these tumors often express PD-L1, and MCPyV-specific T cells express PD-1.

Methods: In this multicenter, phase 2, noncontrolled study, we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab (anti-PD-1) at a dose of 2 mg per kilogram of body weight every 3 weeks. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Efficacy was correlated with tumor viral status, as assessed by serologic and immunohistochemical testing.

Results: A total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patients with at least one evaluation during treatment was 56% (95% confidence interval [CI], 35 to 76); 4 patients had a complete response, and 10 had a partial response. With a median follow-up of 33 weeks (range, 7 to 53), relapses occurred in 2 of the 14 patients who had had a response (14%). The response duration ranged from at least 2.2 months to at least 9.7 months. The rate of progression-free survival at 6 months was 67% (95% CI, 49 to 86). A total of 17 of the 26 patients (65%) had virus-positive tumors. The response rate was 62% among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those with virus-negative tumors (4 of 9 patients). Drug-related grade 3 or 4 adverse events occurred in 15% of the patients.

Conclusions: In this study, first-line therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was associated with an objective response rate of 56%. Responses were observed in patients with virus-positive tumors and those with virus-negative tumors. (Funded by the National Cancer Institute and Merck; ClinicalTrials.gov number, NCT02267603.).
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http://dx.doi.org/10.1056/NEJMoa1603702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927341PMC
June 2016

4-1BB agonism: adding the accelerator to cancer immunotherapy.

Cancer Immunol Immunother 2016 10 31;65(10):1243-8. Epub 2016 Mar 31.

Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford University, 269 Campus Drive, CCSR 1140, Stanford, CA, 94305-5151, USA.

The success of checkpoint inhibitors has validated immunomodulatory agents as a valuable class of anticancer therapeutics. A promising co-stimulatory immunologic target is 4-1BB, or CD137, a member of the tumor necrosis factor receptor superfamily. Ligation of 4-1BB induces an activating signal in CD8(+) T cells and natural killer cells, resulting in increased pro-inflammatory cytokine secretion, cytolytic function, and antibody-dependent cell-mediated cytotoxicity. Targeting 4-1BB with agonistic monoclonal antibody (mAb) therapy demonstrated potent antitumor effects in murine tumor models. While anti-4-1BB mAbs have entered clinical trials, optimal efficacy of 4-1BB-targeted agents will inevitably come from combination therapeutic strategies. Checkpoint blockade is a compelling combination partner for 4-1BB agonism. This novel immunotherapeutic approach has the potential to active antitumor immune effectors by a complementary mechanism: simultaneously "removing the brakes" via blocking inhibitory signaling and "stepping on the accelerator" via co-stimulation. While important considerations should be given to 4-1BB-mediated toxicities, the current understanding of 4-1BB biology suggests it may play a key role in advancing the capabilities of cancer combination therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035667PMC
http://dx.doi.org/10.1007/s00262-016-1829-2DOI Listing
October 2016

Immunodynamics: a cancer immunotherapy trials network review of immune monitoring in immuno-oncology clinical trials.

J Immunother Cancer 2016 15;4:15. Epub 2016 Mar 15.

Fred Hutchinson Cancer Research Center, 1100 Eastlake Ave N., E3-300, PO Box 19024, Seattle, WA 98109-1023 USA.

The efficacy of PD-1/PD-L1 targeted therapies in addition to anti-CTLA-4 solidifies immunotherapy as a modality to add to the anticancer arsenal. Despite raising the bar of clinical efficacy, immunologically targeted agents raise new challenges to conventional drug development paradigms by highlighting the limited relevance of assessing standard pharmacokinetics (PK) and pharmacodynamics (PD). Specifically, systemic and intratumoral immune effects have not consistently correlated with standard relationships between systemic dose, toxicity, and efficacy for cytotoxic therapies. Hence, PK and PD paradigms remain inadequate to guide the selection of doses and schedules, both starting and recommended Phase 2 for immunotherapies. The promise of harnessing the immune response against cancer must also be considered in light of unique and potentially serious toxicities. Refining immune endpoints to better inform clinical trial design represents a high priority challenge. The Cancer Immunotherapy Trials Network investigators review the immunodynamic effects of specific classes of immunotherapeutic agents to focus immune assessment modalities and sites, both systemic and importantly intratumoral, which are critical to the success of the rapidly growing field of immuno-oncology.
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http://dx.doi.org/10.1186/s40425-016-0118-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791805PMC
March 2016

Harnessing the innate immune system to treat cancer: enhancement of antibody-dependent cellular cytotoxicity with anti-CD137 Ab.

Chin Clin Oncol 2016 Feb;5(1)

Division of Oncology, Department of Medicine, Stanford University, CCSR Building, Room 1110, Stanford, CA 94305, USA.

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http://dx.doi.org/10.3978/j.issn.2304-3865.2016.02.05DOI Listing
February 2016

CD44+ Cells in Head and Neck Squamous Cell Carcinoma Suppress T-Cell-Mediated Immunity by Selective Constitutive and Inducible Expression of PD-L1.

Clin Cancer Res 2016 07 10;22(14):3571-81. Epub 2016 Feb 10.

Division of Head and Neck Surgery, Department of Otolaryngology, Stanford Cancer Institute, Stanford, California. Program in Immunology, Stanford University School of Medicine, Stanford, California. Stanford Cancer Institute, Stanford, California. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.

Purpose: Human tumors consist of heterogeneous populations of cells with distinct marker expression and functional properties. In squamous cell carcinoma of the head and neck (SCCHN), CD44 is a well-characterized marker of a resilient subpopulation of cells associated with increased tumorigenesis, radioresistance, and chemoresistance. Evidence indicates that these cells have an immunosuppressive phenotype; however, mechanisms have been elusive.

Experimental Design: Using primary human SCCHN tumor samples and patient-derived xenografts, we examined the phenotypes of subsets of tumor cells and investigated mechanisms regulating their immunogenicity.

Results: CD44(+) cells in primary human SCCHN were found to have an epithelial-to-mesenchymal (EMT) phenotype and were less immunogenic than CD44(-) cells when cultured with autologous CD8(+) tumor-infiltrating T cells. Selective expression of the programmed death-ligand 1 (PD-L1) was observed on CD44(+) cells compared with CD44(-) cells and was associated with constitutive phosphorylation of STAT3 on CD44(+) cells. Importantly, inhibition of STAT3 decreased expression of PD-L1 on CD44(+) cells. IFNγ treatment preferentially induced even further PD-L1 expression on CD44(+) cells and was associated with enhanced IFNγ receptor expression and phosphorylation of STAT1. Finally, the decreased immunogenicity of CD44(+) cells was partially reversed by antibody blockade of the programmed death 1 (PD-1) receptor, indicating that the differences in PD-L1 expression between CD44(+) and CD44(-) cells are biologically and clinically relevant.

Conclusions: Our findings provide a mechanism by which long-lived CD44(+) tumor-initiating cells can selectively evade host immune responses and provide rationale for targeting the PD-1 pathway in the adjuvant therapy setting of SCCHN. Clin Cancer Res; 22(14); 3571-81. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623594PMC
July 2016

In situ vaccination for the treatment of cancer.

Immunotherapy 2016 9;8(3):315-30. Epub 2016 Feb 9.

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Vaccination has had a tremendous impact on human health by harnessing the immune system to prevent and eradicate infectious diseases and this same approach might be used in cancer therapy. Cancer vaccine development has been slowed hindered by the paucity of universal tumor-associated antigens and the difficulty in isolating and preparing individualized vaccines ex vivo. Another approach has been to initiate or stimulate an immune response in situ (at the tumor site) and thus exploit the potentially numerous tumor-associated antigens there. Here, we review the many approaches that have attempted to accomplish effective in situ vaccination, using intratumoral administration of immunomodulators to increase the numbers or activation state of either antigen present cells or T cells within the tumor.
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http://dx.doi.org/10.2217/imt.15.120DOI Listing
December 2016

Rationale for anti-CD137 cancer immunotherapy.

Eur J Cancer 2016 Feb 2;54:112-119. Epub 2016 Jan 2.

Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305 USA. Electronic address:

The consideration of the complex interplay between the tumour microenvironment (TME) and the immune response is the key for designing effective immunotherapies. Therapeutic strategies that harness co-stimulatory receptors have recently gained momentum in the clinic. One such strategy with promising clinical applications is the targeting of CD137, a member of the tumour necrosis factor receptor superfamily. Its expression on both innate and adaptive immune cells, coupled with its unique ability to potentiate antitumour responses through modulating the TME and to ameliorate autoimmune responses, has established it as an appealing target. In this review, we will discuss the various CD137-targeted immunotherapeutics that have reached clinical development, with a focus on recent advances and novel modalities such as CD137 chimeric antigen receptors and CD137 bispecific antibodies. We will also highlight the effect of CD137 targeting on the TME and discuss the importance of probing TME changes for predicting and testing the efficacy of CD137-mediated immunotherapy.
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http://dx.doi.org/10.1016/j.ejca.2015.09.026DOI Listing
February 2016

Natural Killer Cell Immunomodulation: Targeting Activating, Inhibitory, and Co-stimulatory Receptor Signaling for Cancer Immunotherapy.

Front Immunol 2015 2;6:601. Epub 2015 Dec 2.

Division of Oncology, Department of Medicine, Stanford University , Stanford, CA , USA.

There is compelling clinical and experimental evidence to suggest that natural killer (NK) cells play a critical role in the recognition and eradication of tumors. Efforts at using NK cells as antitumor agents began over two decades ago, but recent advances in elucidating NK cell biology have accelerated the development of NK cell-targeting therapeutics. NK cell activation and the triggering of effector functions is governed by a complex set of activating and inhibitory receptors. In the early phases of cancer immune surveillance, NK cells directly identify and lyse cancer cells. Nascent transformed cells elicit NK cell activation and are eliminated. However, as tumors progress, cancerous cells develop immunosuppressive mechanisms that circumvent NK cell-mediated killing, allowing for tumor escape and proliferation. Therapeutic intervention aims to reverse tumor-induced NK cell suppression and sustain NK cells' tumorlytic capacities. Here, we review tumor-NK cell interactions, discuss the mechanisms by which NK cells generate an antitumor immune response, and discuss NK cell-based therapeutic strategies targeting activating, inhibitory, and co-stimulatory receptors.
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http://dx.doi.org/10.3389/fimmu.2015.00601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667030PMC
December 2015

Scientific Significance of Clinically Insignificant FcγRIIIa-V158F Polymorphism.

Clin Cancer Res 2016 Feb 18;22(4):787-9. Epub 2015 Dec 18.

Department of Medicine, Division of Oncology, Stanford University, Stanford, California.

Kenkre and colleagues report the absence of correlation between FcγRIIIa-V158F polymorphism and rituximab response in follicular lymphoma patients, a result which is in contrast with prior studies. This discrepancy recalls that many other factors (from the host and from the tumor) may influence the efficacy of rituximab in vivo.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2777DOI Listing
February 2016

A quantitative analysis of therapeutic cancer vaccines in phase 2 or phase 3 trial.

J Immunother Cancer 2015 17;3:48. Epub 2015 Nov 17.

Department of Medicine, Division of Oncology, Stanford University, CCSR 1110, 269 Campus Drive, Stanford, California 94305 USA.

Despite the progress that has been made in other forms of cancer therapy, Provenge® (Sipuleucel-T) is the only FDA-approved vaccine for the treatment of cancer. To understand the current landscape of therapeutic oncology vaccines we performed a quantitative analysis of phase 2 and phase 3 therapeutic cancer vaccine trials. We highlight shifts in trends for the vaccine platforms examined, common adjuvant use, target indications, antibody or treatment combinations between past and recent trials as well as discuss the relationship between these trends and ratio between the number of phase 3: phase 2 for different vaccine platforms. Despite the poor success rate in vaccine approvals, registration of phase 3 trials between 2010 and 2014 were stable indicating continued investment and efforts towards development of immunotherapeutic vaccines.
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http://dx.doi.org/10.1186/s40425-015-0093-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647658PMC
November 2015

Critical issues in cancer vaccine trial design.

Vaccine 2015 Dec 19;33(51):7386-7392. Epub 2015 Sep 19.

San Antonio Military Medical Consortium, Department of Surgical Oncology, Fort Sam Houston, Houston, TX, USA.

As the clinical experience with cancer vaccines and cancer immunotherapy increases, there are important lessons that can be learned from the successes and failures of past trials. Many lessons affect the design and conduct of clinical trials themselves. Appropriate patient selection, clinical trial design, immunologic monitoring, and appropriate endpoints are all essential to the efficiency and success of bringing cancer vaccines from conception to clinical use.
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http://dx.doi.org/10.1016/j.vaccine.2015.09.019DOI Listing
December 2015

In-situ tumor vaccination: Bringing the fight to the tumor.

Hum Vaccin Immunother 2015 ;11(8):1901-9

a OncoSec Medical Inc. ; San Diego , CA USA.

After decades of development in the shadow of traditional cancer treatment, immunotherapy has come into the spotlight. Treatment of metastatic tumors with monoclonal antibodies to T cell checkpoints like programed cell death 1 (PD-1) or its ligand, (PD-L1), have resulted in significant clinical responses across multiple tumor types. However, these therapies fail in the majority of patients with solid tumors, in particular those who lack PD1(+)CD8(+) tumor-infiltrating lymphocytes within their tumors. Intratumoral "in situ vaccination" approaches seek to enhance immunogenicity, generate tumor infiltrating lymophcytes (TIL) and drive a systemic anti-tumor immune response, directed against "unvaccinated," disseminated tumors. Given the emerging picture of intratumoral immunotherapy as safe and capable of delivering systemic efficacy, it is anticipated that these approaches will become integrated into future multi-modality therapy.
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http://dx.doi.org/10.1080/21645515.2015.1049779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635874PMC
May 2016

Boosting Cancer Immunotherapy with Anti-CD137 Antibody Therapy.

Clin Cancer Res 2015 Jul 23;21(14):3113-20. Epub 2015 Apr 23.

Division of Oncology, Department of Medicine, Stanford University, Stanford, California.

In the past 5 years, immunomodulatory antibodies have revolutionized cancer immunotherapy. CD137, a member of the tumor necrosis factor receptor superfamily, represents a promising target for enhancing antitumor immune responses. CD137 helps regulate the activation of many immune cells, including CD4(+) T cells, CD8(+) T cells, dendritic cells, and natural killer cells. Recent studies indicate that the antitumor efficacy of therapeutic tumor-targeting antibodies can be augmented by the addition of agonistic antibodies targeting CD137. As ligation of CD137 provides a costimulatory signal in multiple immune cell subsets, combination therapy of CD137 antibody with therapeutic antibodies and/or vaccination has the potential to improve cancer treatment. Recently, clinical trials of combination therapies with agonistic anti-CD137 mAbs have been launched. In this review, we discuss the recent advances and clinical promise of agonistic anti-CD137 monoclonal antibody therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-0263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422104PMC
July 2015

Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK.

Proc Natl Acad Sci U S A 2015 Mar 17;112(9):E966-72. Epub 2015 Feb 17.

Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305-5151; and

Monoclonal antibodies can block cellular interactions that negatively regulate T-cell immune responses, such as CD80/CTLA-4 and PD-1/PD1-L, amplifying preexisting immunity and thereby evoking antitumor immune responses. Ibrutinib, an approved therapy for B-cell malignancies, is a covalent inhibitor of BTK, a member of the B-cell receptor (BCR) signaling pathway, which is critical to the survival of malignant B cells. Interestingly this drug also inhibits ITK, an essential enzyme in Th2 T cells and by doing so it can shift the balance between Th1 and Th2 T cells and potentially enhance antitumor immune responses. Here we report that the combination of anti-PD-L1 antibody and ibrutinib suppresses tumor growth in mouse models of lymphoma that are intrinsically insensitive to ibrutinib. The combined effect of these two agents was also documented for models of solid tumors, such as triple negative breast cancer and colon cancer. The enhanced therapeutic activity of PD-L1 blockade by ibrutinib was accompanied by enhanced antitumor T-cell immune responses. These preclinical results suggest that the combination of PD1/PD1-L blockade and ibrutinib should be tested in the clinic for the therapy not only of lymphoma but also in other hematologic malignancies and solid tumors that do not even express BTK.
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http://dx.doi.org/10.1073/pnas.1500712112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352777PMC
March 2015

Ibrutinib enhances the antitumor immune response induced by intratumoral injection of a TLR9 ligand in mouse lymphoma.

Blood 2015 Mar 6;125(13):2079-86. Epub 2015 Feb 6.

Department of Medicine, Division of Oncology, Stanford University, Stanford, CA.

We have designed a novel therapeutic approach for lymphoma that combines targeted kinase inhibition with in situ vaccination. Intratumoral injection of an unmethylated cytosine guanine dinucleotide (CpG)-enriched oligodeoxynucleotide, an agonist for the toll-like receptor 9 (TLR9), induces the activation of natural killer cells, macrophages, and antigen presenting cells that control tumor growth at the local site. Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase, a key enzyme in the signaling pathway downstream of B-cell receptor, is an effective treatment against many types of B-cell lymphomas. The combination of intratumoral injection of CpG with systemic treatment by ibrutinib resulted in eradication of the tumors not only in the injected site, but also at distant sites. Surprisingly, this combinatorial antitumor effect required an intact T-cell immune system since it did not occur in nude, severe combined immunodeficiency, or T-cell depleted mice. Moreover, T cells from animals treated with intratumoral CpG and ibrutinib prevented the outgrowth of newly injected tumors. This result suggests that ibrutinib can induce immunogenic cell death of lymphoma cells and that concomitant stimulation of antigen-presenting cells in the tumor microenvironment by toll-like receptor ligands can lead to a powerful systemic antitumor immune response.
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http://dx.doi.org/10.1182/blood-2014-08-593137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375105PMC
March 2015

Dual antibody therapy to harness the innate anti-tumor immune response to enhance antibody targeting of tumors.

Curr Opin Immunol 2015 Apr 7;33:1-8. Epub 2015 Jan 7.

Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305, USA. Electronic address:

Cancer immunotherapy is a rapidly evolving field that offers a novel paradigm for cancer treatment: therapies focus on enhancing the immune system's innate and adaptive anti-tumor response. Early immunotherapeutics have achieved impressive clinical outcomes and monoclonal antibodies are now integral to therapeutic strategies in a variety of cancers. However, only recently have antibodies targeting innate immune cells entered clinical development. Innate immune effector cells play important roles in generating and maintaining antitumor immunity. Antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) are important innate immune mechanisms for tumor eradication. These cytolytic processes are initiated by the detection of a tumor-targeting antibody and can be augmented by activating co-stimulatory pathways or blocking inhibitory signals on innate immune cells. The combination of FDA-approved monoclonal antibodies with innate effector-targeting antibodies has demonstrated potent preclinical therapeutic synergy and early-phase combinatorial clinical trials are ongoing.
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http://dx.doi.org/10.1016/j.coi.2014.12.010DOI Listing
April 2015

Enhancement of antibody-dependent cell mediated cytotoxicity: a new era in cancer treatment.

Immunotargets Ther 2015 15;4:91-100. Epub 2015 May 15.

Division of Oncology, Stanford School of Medicine, Stanford University, Stanford, CA, USA.

The therapeutic efficacy of some anti-tumor monoclonal antibodies (mAbs) depends on the capacity of the mAb to recognize the tumor-associated antigen and induce cytotoxicity via a network of immune effector cells. This process of antibody-dependent cell-mediated cytotoxicity (ADCC) against tumor cells is triggered by the interaction of the fragment crystallizable (Fc) portion of the mAb with the Fc receptors on effector cells like natural killer cells, macrophages, γδ T cells, and dendritic cells. By augmenting ADCC, the antitumor activity of mAbs can be significantly increased. Currently, identifying and developing therapeutic agents that enhance ADCC is a growing area of research. Combining existing tumor-targeting mAbs and ADCC-promoting agents that stimulate effector cells will translate to greater clinical responses. In this review, we discuss strategies for enhancing ADCC and emphasize the potential of combination treatments that include US Food and Drug Administration-approved mAbs and immunostimulatory therapeutics.
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http://dx.doi.org/10.2147/ITT.S61292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918249PMC
July 2016

Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients.

Nature 2014 Nov;515(7528):563-7

Dana-Farber/Brigham and Women's Cancer Center, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.

The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the 'cancer immunity cycle' by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing. The PD-L1-PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.
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http://dx.doi.org/10.1038/nature14011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836193PMC
November 2014

Diffuse high intensity PD-L1 staining in thymic epithelial tumors.

J Thorac Oncol 2015 Mar;10(3):500-8

*Division of Oncology, Department of Internal Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA; †Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA; ‡Department of Pathology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA; and §Department of Health and Research Policy, Stanford University School of Medicine, Stanford, CA.

Introduction: Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has well-established clinical activity across many tumor types. PD-L1 protein expression by immunohistochemistry is emerging as a predictive biomarker of response to these therapies. Here, we examine PD-L1 expression in a thymic epithelial tumor (TET) tissue microarray (TMA).

Methods: The TMA contained 69 TETs and 17 thymic controls, with each case represented by triplicate cores. The TMA was stained with rabbit monoclonal antibody (clone 15; Sino Biological, Beijing, China) to human PD-L1. PD-L1 staining was scored based on intensity as follows: 0 = none, 1 = equivocal/uninterpretable, 2 = weak, and 3 = intermediate-strong. Those cases with all cores scoring three in the epithelial component were categorized as PD-L1 high and the remaining as PD-L1 low.

Results: PD-L1 high scores were more frequent in TETs than in controls (68.1% versus 17.6%; p = 0.0036). PD-L1 scores and histology were significantly correlated, with higher intensity staining in World Health Organization (WHO). B2/B3/C TETs. Only 14.8% of TETs had PD-L1 staining of associated lymphocytes. In an adjusted analysis (age/sex), PD-L1 high TETs had a significantly worse overall survival (hazard ratio: 5.40, 95% confidence interval: 1.13-25.89; p = 0.035) and a trend for worse event-free survival (hazard ratio: 2.94, 95% confidence interval: 0.94-9.24; p = 0.064).

Conclusions: PD-L1 expression was present in all cases of TETs within the epithelial component but only in a minority in the lymphocytic component. TETs stained more intensely for PD-L1 than in controls, and PD-L1 high TETs were associated with more aggressive histology and worse prognosis. This study lends rationale to a clinical trial with anti-PD-1/PD-L1 therapy in this rare tumor type.
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http://dx.doi.org/10.1097/JTO.0000000000000429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720257PMC
March 2015

Child abuse, disruptive behavior disorders, depression, and salivary cortisol levels among institutionalized and community-residing boys in Mongolia.

Asia Pac Psychiatry 2015 Mar 3;7(1):7-19. Epub 2014 Jun 3.

Department of Anthropology, Emory University, Atlanta, GA, USA.

Introduction: Hypothalamic-pituitary-adrenal (HPA) axis activity is related to childhood disruptive behavior disorders and to exposure to abuse and neglect. This study explores the relationship of diurnal salivary cortisol levels with oppositional defiant disorder (ODD) and caregiver attitudes toward physical punishment among boys in Mongolia.

Methods: Salivary cortisol was collected in the home or institution 4 times daily for 4 days from 46 boys, aged 4-10 years, in Ulaanbaatar, Mongolia. Caregivers rated child disruptive behavior symptoms, attitudes toward physical punishment, and community violence exposures. Mixed effects models were used to estimate the association of psychopathology and caregiver attitudes with salivary cortisol levels.

Results: Boys meeting criteria for ODD displayed consistently lower diurnal salivary cortisol levels compared to boys without ODD diagnoses. Controlling for ODD diagnosis, boys with depression showed higher cortisol levels throughout the day. No other diagnosis was associated with cortisol levels. Psychiatric diagnosis accounted for 17% of between individual variations in cortisol levels unexplained by the covariates. In a separate model, caregivers' beliefs regarding physical punishment accounted for 11% of between individual differences: boys with caregivers who stated physical punishment was necessary for discipline displayed hypocortisolism. Institutionalization did not associate with cortisol levels.

Discussion: Salivary cortisol data from a non-Western naturalistic setting support an association of reduced basal HPA activity with disruptive behavior disorders and caregiver attitudes toward discipline. These findings suggest HPA functioning may be a reflection of or mediate disruptive behavior disorders in children across ethnic and cultural settings.
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http://dx.doi.org/10.1111/appy.12141DOI Listing
March 2015