Stephen Gottschalk

• MD
• Chair at St. Jude Children's Research Hospital

Key Points Allogeneic stem cell transplant is a well-tolerated and useful therapeutic option for relapsed/refractory pediatric NHL. NHL histological subtype and disease status at time of transplant influence outcomes.

Cytomegalovirus (CMV) infections remain a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT), and standard antiviral therapies are associated with significant side effects and development of drug-resistant mutants. Adoptively transferred donor-derived CMV-specific T cells (CMVSTs) can provide an a...

Background: Patients with advanced sarcoma have limited treatment options and poor survival. In our phase 1 dose-escalation trial, intravenous administration of up to 1x108/m2autologous HER2-CAR T cells in patients with HER2+ sarcoma was safe. The goal of the current study is to evaluate if lymphodepleting chemotherapy can safely improve the expans...

Background: Patients with advanced sarcoma have limited treatment options and poor survival. In our phase 1 dose-escalation trial, intravenous administration of up to 1x108/m2autologous HER2-CAR T cells in patients with HER2+ sarcoma was safe. The goal of the current study is to evaluate if lymphodepleting chemotherapy can safely improve the expans...

BACKGROUND: T cells immunotherapy holds the promise to improve outcomes for pediatric brain tumor patients. We have an interest in cell therapy with T cells expressing chimeric antigen receptors (CARs). CAR T cells recognize cell surface antigens. One goal of our study is to evaluate the cell surface expression of five potential CAR targets: IL13Ra...

High grade gliomas (HGG) remain some of the most difficult to treat pediatric malignancies resulting in dismal outcomes. As even the best treatments currently available show poor efficacy and high toxicity, there is an urgent need to develop new treatment approaches. Immunotherapy with T cells expressing chimeric antigen receptors (CARs) specific f...

Background Allogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy wi...

Introduction HSCT is a curative option for patients with high-risk ALL but relapse remains the major cause of treatment failure. CD19 CAR T cells have shown remarkable efficacy in treating leukemic relapse post-HSCT but their use is limited to CD19+ malignancies and antigen negative relapses are increasingly being reported. To overcome these limita...

Cancer immunotherapy, including immune checkpoint inhibitors, exerts beneficial effects in cancer patients. However, immune checkpoint inhibitors are only advantageous for a limited population of cancer patients. Therefore, companion diagnostics are needed in order to identify patients for whom these therapies are effective. In the present study, w...

Immunotherapy with chimeric antigen receptor (CAR) T cells offers a promising method to improve cure rates and decrease morbidities for patients with cancer. In this regard, CD19-specific CAR T cell therapies have achieved dramatic objective responses for a high percent of patients with CD19-positive leukemia or lymphoma. Most patients with solid t...

While impressive clinical responses have been observed using chimeric antigen receptor (CAR) T cells targeting CD19+ hematologic malignancies, limited clinical benefit has been observed using CAR T cells for a variety of solid tumors. Results of clinical studies have highlighted several obstacles which CAR T cells face in the context of solid tumor...

Solid tumors are refractory to cellular immunotherapies in part because they contain suppressive immune effectors such as myeloid‑derived suppressor cells (MDSCs) that inhibit cytotoxic lymphocytes. Strategies to reverse the suppressive tumor microenvironment (TME) should also attract and activate immune effectors with antitumor activity. To addres...

The efficacy of T cells expressing chimeric antigen receptors (CARs) for solid tumors has been limited by insufficient CAR T cell expansion and persistence. The use of virus-specific T cells (VSTs) as carriers for CARs may overcome this limitation since CAR-VSTs can be boosted by viral vaccines or oncolytic viruses. However, there is limited unders...

BACKGROUND Malignant gliomas (MG) are the most common and difficult-to-treat adult brain tumors. The outstanding efficacy of chimeric antigen receptor (CAR)-modified T cells against hematological malignancies gives hope that they can be programmed to target and eradicate solid tumors like MG. We recently demonstrated that murine CAR.CD28.ζ T cells...

Background aims: EBV type II latency tumors, such as Hodgkin lymphoma (HL), Non-Hodgkin lymphoma (NHL) and nasopharyngeal carcinoma, express a limited array of EBV antigens including Epstein-Barr nuclear antigen (EBNA)1, latent membrane protein (LMP)1, LMP2, and BamH1-A right frame 1 (BARF1). Adoptive immunotherapy for these malignancies have focu...

There is no established salvage regimen for pediatric patients with relapsed nasopharyngeal carcinoma (NPC) and outcomes are dismal. We performed a multicenter retrospective review to determine outcomes after first salvage therapy for pediatric patients with relapsed NPC. Fourteen patients were treated with varied regimens. Two of the 14 patients r...

Engineering T cells for the immunotherapy for pediatric solid tumorsImmunotherapy with genetically modified T cells holds the promise to improve outcome for pediatric cancer patients who currently cannot be cured. In addition, T-cell therapy has the potential to reduce treatment-related complication for all patients. Cell therapy with T cells, gene...

Autologous T cells targeting Epstein Barr virus (EBV) latent membrane proteins (LMPs) have shown safety and efficacy for the treatment of patients with type II latency EBV-associated lymphomas who have failed standard therapies, including high dose chemotherapy followed by autologous stem cell rescue. However, the safety and efficacy of allogeneic...

There remains an urgent need for the noninvasive tracking of transfused chimeric antigen receptor (CAR) T cells to determine their biodistribution, viability, expansion, and antitumor functionality. DOTA antibody reporter 1 (DAbR1) comprises a single-chain fragment of the antilanthanoid-DOTA antibody 2D12.5/G54C fused to the human CD4-transmembrane...

Adoptive cell therapy with genetically modified T cells holds the promise to improve outcomes for children with recurrent/refractory solid tumors and has the potential to reduce treatment complications for all patients. Although T cells that express chimeric antigen receptors (CARs) specific for CD19 have had remarkable success for B-cell-derived m...

Background: Chronic hepatitis B virus (HBV) infection remains incurable. Although HBsAg-specific chimeric antigen receptor (HBsAg-CAR) T cells have been generated, they have not been tested in animal models with authentic HBV infection. Methods: We generated a novel CAR targeting HBsAg and evaluated its ability to recognize HBV+ cell lines and H...

There is a lack of consensus regarding the role and method of Hematopoietic Stem Cell Transplantation (HSCT) on patients with Chronic Granulomatous Disease (CGD), Long term follow up after HSCT in these patient population is essential in order to know its potential complications and decide who will benefit the most from HSCT. We report the outcome...

Introduction: The outcome for patients with glioblastoma (GBM) remains poor, and there is an urgent need to develop novel therapeutic approaches. T cells genetically modified with chimeric antigen receptor (CARs) hold the promise to improve outcomes since they recognize and kill cells through different mechanisms than conventional therapeutics. Are...

Hematopoietic stem cell transplantation (HSCT) is the only curative option for a subset of patients with high-risk or relapsed Acute Lymphoblastic Leukemia (ALL). Given evolving practices, it is important to continually evaluate outcomes for pediatric ALL following HSCT. Outcomes after HSCT are influenced by the type of donor used as this determine...

Glioblastoma is the most aggressive primary brain tumor in humans and is virtually incurable with conventional therapies. Chimeric antigen receptor (CAR) T cell therapy targeting the glioblastoma antigen EphA2 is an attractive approach to improve outcomes because EphA2 is expressed highly in glioblastoma but only at low levels in normal brain tissu...

In order to fully harness the potential of immunotherapy with chimeric antigen receptor (CAR)-modified T cells, pre-clinical studies must be conducted in immunocompetent animal models that closely mimic the immunosuppressive malignant glioma (MG) microenvironment. Thus, the goal of this project was to study the in vivo fate of T cells expressing CA...

Purpose Transforming growth factor-β (TGF-β) production in the tumor microenvironment is a potent and ubiquitous tumor immune evasion mechanism that inhibits the expansion and function of tumor-directed responses; therefore, we conducted a clinical study to discover the effects of the forced expression of a dominant-negative TGF-β receptor type 2 (...

There is a need to improve outcomes for patients with recurrent and/or refractory hematological malignancies. Immunotherapy holds the promise to meet this need since it does not rely on the cytotoxic mechanism of conventional therapies. Among different forms of immunotherapy, redirecting T cells to hematological malignancies with bispecific antibod...

Epstein Barr virus (EBV) is a human gamma herpes virus that establishes latency in B cells after primary infection. EBV generally only causes a mild, self-limiting viral illness but is also associated with several malignancies including posttransplantation lymphoproliferative disorder in the immunosuppressed host as well as Hodgkin and non-Hodgkin...

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by a triad of immunodeficiency, eczema and thrombocytopenia. Currently, hematopoietic stem cell transplant (HSCT) is the most reliable curative treatment with excellent results for patients with HLA-matched family or unrelated donors. However, even after fully myeloablative pr...

Introduction: Achieving better disease control in patients diagnosed with acute myeloid leukemia (AML) has proven challenging. Overall survival has been impacted by addressing treatment related mortality with focused supportive care measures. Despite this improvement, it remains difficult to induce durable leukemia remissions despite aggressive che...

In solid tumors, chimeric antigen receptor (CAR)-modified T cells must overcome the challenges of the immunosuppressive tumor microenvironment. We hypothesized that pre-treating tumors with our binary oncolytic adenovirus (CAd), which produces local oncolysis and expresses immunostimulatory molecules, would enhance the antitumor activity of HER2-sp...

Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a co...

T cells expressing CD19-specific chimeric antigen receptors (CARs) with endodomains that encode a signaling domain derived from CD3zeta and CD28 or 41BB have potent antitumor activity in early phase clinical studies for B-cell malignancies. Besides CD19-specific CARs, other approaches are actively being pursued to redirect T cells to CD19, includin...

Adoptive immunotherapy with T cells expressing chimeric antigen receptors (CAR) has had limited success for solid tumors in early-phase clinical studies. We reasoned that introducing into CAR T cells an inducible costimulatory (iCO) molecule consisting of a chemical inducer of dimerization (CID)–binding domain and the MyD88 and CD40 signaling domai...

Purpose Improvement of cure rates for patients treated with allogeneic hematopoietic stem-cell transplantation (HSCT) will require efforts to decrease treatment-related mortality from severe viral infections. Adoptively transferred virus-specific T cells (VSTs) generated from eligible, third-party donors could provide broad antiviral protection to...

Current therapies against hepatitis B virus (HBV) do not reliably cure chronic infection, necessitating new therapeutic approaches. The T cell response can clear HBV during acute infection, and the adoptive transfer of antiviral T cells during bone marrow transplantation can cure patients of chronic HBV infection. To redirect T cells to HBV-infecte...

Movie S2. GPC3-ENG MSCs.CD80+41BBL Do Not Redirect T Cells to Kill GPC3− Tumor Cells Time-lapse confocal microscopy video (quantitative data is presented in Fig. 6B). GPC3-ENG MSCs.CD80+41BBL (green) do not redirect T cells to kill GPC3− cancer cells (A549) as judged by PI incorporation. Images were acquired every 5 minutes; video length: 12 h.

Time-lapse confocal microscopy video (quantitative data is presented in Fig. 6B). GPC3-ENG MSCs.CD80+41BBL (green) redirect T cells to kill GPC3+ cancer cells (HUH7) as judged by PI incorporation. Images were acquired every 5 minutes; video length: 12 h.

The successful immunotherapy of acute myeloid leukemia (AML) has been hampered because most potential antigenic targets are shared with normal hematopoietic stem cells (HSCs), increasing the risk of sustained and severe hematopoietic toxicity following treatment. C-type lectin-like molecule 1 (CLL-1) is a membrane glycoprotein expressed by >80% of...

The outcome for advanced stage hepatocellular carcinoma (HCC) remains poor, highlighting the need for novel therapies. Genetically modified mesenchymal stem cells (MSCs) are actively being explored as cancer therapeutics due to their inherent ability to migrate to tumor sites. We reasoned that MSCs can be genetically modified to redirect T cells to...

The goal of this project is to develop T-cells expressing IL13Rα2-specific chimeric antigen receptor (CAR) as an effective immunotherapy for diffuse intrinsic pontine glioma (DIPG) and glioblastoma (GBM), the most aggressive, highly lethal, primary human brain tumors in children. We recently demonstrated that IL13Rα2-CARs with a CD28.ζ endodomain h...

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is virtually incurable with conventional therapies. Immunotherapy with T cells expressing GBM-specific chimeric antigen receptors (CARs) is an attractive approach to improve outcomes. Although CAR T cells targeting GBM antigens such as IL13Ralpha2 (interleukin 13 Receptor S...

10508 Background: Outcome for patients with advanced sarcoma is extremely poor and treatment options are limited. Encouragingly, in our phase 1 dose-escalation trial (Ahmed et al, JCO 2015), systemic administration of up to 1x10 ⁸ /m ² autologous HER2-CAR T cells in patient with HER2+ sarcoma was safe. While T cells did not expand, 4/19 evaluable p...

Importance: Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited. Objective: To determine whether the systemic administration of HER2-specific chimeric antigen receptor (CAR)-modified virus-specific T cells (VSTs) is safe and whether these cells have antiglioblastoma activity. Design, setting, and participant...

The outstanding efficacy of T cells modified to express chimeric antigen receptors (CAR) for hematological malignancies promises hope that they can be programmed to target and kill solid tumors. As the current standard of care for glioblastoma (GBM) only extends patient survival minimally, CARs can provide an exciting new option for the treatment o...

http://www.bbmt.org/article/S1083-8791(16)31002-3/abstract

As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibo...

Chimeric antigen receptor-modified T cells (CAR T-cells) produce pro-inflammatory cytokines that increase expression of T cell checkpoint signals such as PD-L1, which may inhibit their functionality against solid tumors. In this study, we evaluated in human tumor xenograft models the pro-inflammatory properties of an oncolytic adenovirus (Onc.Ad) w...

In this issue of Blood, Braig et al have identified a novel mechanism of CD19-targeted immune escape.

Poster presentation from the 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer.

The goal of this project is to develop T cells expressing IL13Rα2-specific chimeric antigen receptor (CAR) as an effective immunotherapy for glioblastoma (GBM), the most aggressive, primary brain tumor in humans, in which outcome remains poor. We recently demonstrated that IL13Rα2-CARs with a CD28.z endodomain had potent anti-GBM activity in precli...

T cells engineered to express CD19-specific chimeric antigen receptors (CARs) have shown breakthrough clinical successes in patients with B-cell lymphoid malignancies. However, the therapeutic efficacy of CAR T cells in solid tumors is yet to be achieved. In this study we systematically evaluated a series of CAR constructs targeting glypican-3 (GPC...

In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of...

Immunotherapy with CD123-specific T-cell engager proteins or with T cells expressing CD123-specific chimeric antigen receptors is actively being pursued for acute myeloid leukemia. T cells secreting bispecific engager molecules (ENG-T cells) may present a promising alternative to these approaches. To evaluate therapeutic potential, we generated T c...

T cells expressing chimeric antigen receptors (CARs) or the infusion of bispecific T-cell engagers (BITEs) have shown antitumor activity in humans for CD19-positive malignancies. While BITEs redirect the large reservoir of resident T cells to tumors, CAR T cells rely on significant in vivo expansion to exert antitumor activity. We have shown that i...

BACKGROUND: Glioblastoma (GBM) is the most aggressive primary brain tumor in humans, and is virtually incurable with conventional therapies. Immunotherapy with T cells expressing chimeric antigen receptors (CARs) specific for the GBM antigen IL13Rα2 is an attractive approach to improve outcomes. We recently generated the first scFv-based CAR that i...

Table of contents A1 Hope and despair in the current treatment of nasopharyngeal cancer IB Tan I1 NPC international incidence and risk factors Ellen T Chang I2 Familial nasopharyngeal carcinoma and the use of biomarkers Chien-Jen Chen, Wan-Lun Hsu, Yin-Chu Chien I3 Genetic susceptibility risk factors for sporadic and familial NPC: recent findings A...