Jeffrey Schlom, Ph.D.
Laboratory of Tumor Immunology and Biology
Building 10, Room 8B09
Bethesda, MD 20892-1750
The Laboratory of Tumor Immunology and Biology (LTIB) functions as a multidisciplinary and interdisciplinary translational research programmatic effort with the goal of developing novel immunotherapies for cancer. The LTIB strategic plan focuses on the development of novel immunotherapeutics, not only as monotherapies, but more importantly, in combination with other immune-mediating modalities, and other conventional or experimental therapies, as part of an immuno-oncology programmatic effort. Within this effort are several research groups and a clinical trials group, and multiple collaborations with intramural and extramural scientific and clinical investigators, and with investigators in the private sector.
The LTIB program takes advantage of the uniqueness of the NCI intramural program in that it spans high-risk basic discovery research in immunology and tumor biology, through preclinical translational research, to paradigm-shifting clinical trials. Focus is placed on the design and development of novel 'off-the-shelf' recombinant immunotherapeutics and immunomodulators that can be used in clinical studies at numerous institutions, and do not involve costly and labor-intensive ex vivo manipulations that can be carried out in only one or two centers. This is accomplished in part via Cooperative Research and Development Agreements (CRADAs) with partners in the private sector. The immunotherapeutics and immune modulators that we have developed have also enabled multiple collaborations with clinical investigators at extramural Cancer Centers.
While the use of checkpoint inhibitor monoclonal antibodies (MAb) has shown clear clinical benefit in patients with melanoma and some other malignancies, in the vast majority of solid tumors <20% of patients benefit from this class of therapies. The LTIB is involved in the design and development of a spectrum of immunotherapeutic and immunomodulatory agents. Preclinical studies have been completed or are ongoing with a range of agents, and clinical studies using many of these agents as monotherapies or in combination therapies are either completed, ongoing or planned to begin shortly.
The preclinical and clinical immunotherapy studies employing a spectrum of different immunotherapeutic agents including vaccines, checkpoint inhibitors, immune modulators, and inhibitors of immune suppressive entities have the potential to convert tumors that currently do not respond to checkpoint inhibition monotherapy (so-called “cold tumors”) into permissive immunogenic targets leading to clinical benefit in patients with multiple types of tumors. A major emphasis of these studies is to also better understand the mechanisms of both host immune cell activation and resistance of tumors to immunotherapeutic approaches, both within the tumor microenvironment and in the peripheral immunome. It may also define which patients will respond to combination immunotherapies when interrogated either (a) prior to the initiation of treatment or (b) early in the therapeutic regimen. These studies may also define which patients will most likely develop autoimmune events when the peripheral immunome is interrogated either prior to the initiation of therapy or early in the therapeutic regimen.
Agents under preclinical and clinical investigation as monotherapy or in combination therapies are:
Recombinant vaccines: (a) Poxviral vectors expressing three costimulatory molecules and expressing transgenes for either PSA, CEA plus MUC1, or brachyury. The transcription factor brachyury has been identified as a driver of the epithelial-to-mesenchymal transition (EMT) process, stemness, and resistance to therapy. (b) Admixtures of proprietary recombinant adenovirus vectors containing transgenes for brachyury, CEA, MUC1, PSA, HER-2, and tumor neo-epitopes.
Checkpoint inhibitors: (a) anti-PDL1 (avelumab), (b) anti-PDL1/TGF-betaR2 (TRAP), and (c) agonist antibodies to OX40 and 41BB.
Immune enhancers: (a) IL-15/Ra/Fc immunocytokine (Alt-803), (b) tumor targeting IL-12 immunocytokine (NHS-IL12), and (c) IDO inhibitor.
Inhibitors of immune suppressive entities: (a) anti-IL8 MAb, (b) small molecule IL-8 inhibitor (IL-8 receptor antagonist), and (c) anti-PDL1/TGF-betaR2 (TRAP).
SELECTED RESEARCH ACTIVITIES
The major goals of these studies are (a) to design and develop specific "off-the-shelf" immunotherapeutics for the therapy of human carcinomas, (b) to define strategies in preclinical studies for the use of these immunotherapeutics as part of an immune-oncology platform, and (c) to interrogate so-called "non-immune"-based therapies for their effect on human immune cell subsets to provide the rationale for their combined use, if any, with specific immunotherapeutics.
PD-L1 Checkpoint MAb: Several anti-PD1/PD-L1 monoclonal antibodies (MAbs) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these MAbs is to inhibit PD1 on immune cells interacting with PD-L1 on tumor cells. These MAbs were either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC, however, has been implicated as an important mechanism in several highly effective MAb-mediated cancer therapies. A fully human anti-PD-L1 MAb would potentially be able to block PD-L1/PD1 interactions and also mediate the ADCC lysis of tumor cells. Avelumab is a fully human IgG1 anti-PD-L1 MAb. Studies have demonstrated (a) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (b) IFN-gamma can enhance tumor cell PD-L1 expression and in some cases enhance ADCC tumor cell lysis; (c) purified NK cells are potent effectors for avelumab; (d) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (e) very low levels of avelumab-mediated lysis are seen using whole PBMC as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (f) the addition of IL-12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 MAb and provide the rationale for further studies to enhance avelumab-mediated ADCC activity.
IL-12 Immunocytokine: Targeted delivery of IL-12 might turn this cytokine into a safer, more effective cancer therapeutic. We have described a novel immunocytokine, NHS-IL12, consisting of two molecules of IL-12 fused to a tumor necrosis-targeting human IgG1 (NHS76). NHS-IL12 was superior to recombinant IL-12 when evaluated as an anti-tumor agent in three murine tumor models. Mechanistic studies utilizing immune cell subset-depleting antibodies, flow cytometric methods, and in vitro cytotoxicity and ELISA assays all indicated that the anti-tumor effects of NHS-IL12 were primarily CD8+ T cell-dependent and likely IL-12-mediated. Combining NHS-IL12 radiation, or chemotherapy resulted in greater anti-tumor effects than each individual therapy alone. These preclinical findings provide a rationale for the clinical testing of this immunocytokine, both as a single agent and in combination with vaccines, radiation and chemotherapy.
IL-15 Immunocytokine: We have examined the immunomodulatory and anti-tumor effects of the IL-15/Ra-Fc immunocytokine in tumor-free and highly metastatic tumor-bearing mice. Here, the IL-15/Ra-Fc immunocytokine significantly expanded natural killer (NK) and CD8+ T cells. In examining NK cell subsets, the greatest significant increase was in highly cytotoxic and migrating NK cells, leading to enhanced function on a per-cell basis. CD8+ T cell subset analysis determined that the IL-15/Ra-Fc immunocytokine significantly increased memory CD8+ T cells. In 4T1 breast tumor-bearing mice, the IL-15/Ra-Fc immunocytokine induced significant anti-tumor activity against spontaneous pulmonary metastases, depending on CD8+ T and NK cells, and resulting in prolonged survival. Similar anti-tumor activity was seen in the experimental pulmonary metastasis model of colon carcinoma, particularly when the IL-15/Ra-Fc immunocytokine was combined with a cocktail of checkpoint inhibitors, anti-CTLA-4 and anti-PD-L1.
Brachyury: The epithelial-mesenchymal transition (EMT) has been implicated as an important process in tumor cell invasion, metastasis, and drug resistance. The transcription factor brachyury has recently been described as a driver of EMT of human carcinoma cells. The level of brachyury expression in breast cancer cells was positively associated with their ability to invade the extracellular matrix, efficiently form mammospheres in vitro, and resist the cytotoxic effect of docetaxel. A comparison of survival among breast cancer patients treated with tamoxifen in the adjuvant setting who had tumors with high vs low brachyury mRNA expression demonstrated that high expression of brachyury is associated as an independent variable with higher risk of recurrence and distant metastasis. We also demonstrated that brachyury-specific T cells can lyse human breast carcinoma cells. These studies provide the rationale for the use of a vaccine targeting brachyury for the therapy of human breast cancer, either as a monotherapy or in combination therapies.
We have reported on the generation of a heat-killed recombinant Saccharomyces cerevisiae (yeast) vector expressing the full-length brachyury gene encoding an agonist epitope. Compared to yeast-brachyury (native) devoid of the agonist epitope, the yeast-brachyury (agonist) enhanced the activation of brachyury-specific T cells, which efficiently lysed human carcinoma cells. This vaccine is currently in a clinical study in patients with chordoma.
Tri-Adeno: Phenotypic heterogeneity of human carcinoma lesions, including heterogeneity in expression of tumor-associated antigens (TAAs), is a well-established phenomenon. Carcinoembryonic antigen (CEA), MUC1, and brachyury are diverse TAAs, each of which is expressed on a wide range of human tumors. We have reported on the use of a combination of the three vaccines (designated Tri-Ad5) of Ad5-CEA, Ad5-brachyury and Ad5-MUC1, and demonstrate that there is minimal to no "antigenic competition" in in vitro studies of human dendritic cells, or in murine vaccination studies. These studies support the rationale for the application of Tri-Ad5 as a therapeutic modality to induce immune responses to a diverse range of human TAAs for potential clinical studies.
Bladder Cancer: In this study, an aggressive, bioluminescent orthotopic bladder cancer model, MB49 tumor cells transfected with luciferase (MB49(luc)), was used to study the antitumor effects of avelumab, an antibody to PD-L1. MB49(luc) murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non-muscle invasive, non-metastatic urothelial carcinomas. MB49(luc) bladder tumors are highly positive for the expression of PD-L1, and avelumab administration induced significant (P < 0.05) antitumor effects. These antitumor effects were more dependent on the presence of CD4 than CD8 T cells, as determined by in vivo immune cell depletions. The findings suggest that in this bladder tumor model, interruption of the immune-suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth. This bladder tumor model can be used to further identify host antitumor immune mechanisms and evaluate combinations of immune-based therapies for carcinoma in situ and non-muscle invasive, non-metastatic urothelial carcinoma, to provide the rationale for subsequent clinical studies.
Peripheral Immunoscore: Tumor immunoscore analyses, especially for primary colorectal cancer and melanoma lesions, have provided valuable prognostic information. Metastatic lesions of many carcinoma types, however, are often not easily accessible. We hypothesized that immune cells in peripheral blood may differ among individual patients with metastatic disease, which, in turn, may influence their response to immunotherapy. We thus analyzed immune cell subsets within peripheral blood mononuclear cells to determine if a "peripheral immunoscore" would have any prognostic significance for patients prior to receiving immunotherapy. Patients with metastatic breast cancer were randomized to receive docetaxel +/- PANVAC vaccine. In another trial, prostate cancer patients with metastatic bone lesions were randomized to receive a bone-seeking radionuclide +/- PROSTVAC vaccine. Predefined analyses of "classic" immune cell types (CD4, CD8, NK, Tregs, MDSCs, and ratios) revealed no differences in progression-free survival (PFS) for either arm in both trials. Predefined analyses of refined immune cell subsets for which a biologic function had been previously reported also revealed no significant prognostic value in PFS in patients receiving either docetaxel or radionuclide alone; however, in patients receiving these agents in combination with vaccine, the peripheral immunoscore of refined subsets revealed statistically significant differences in PFS (P < 0.001) for breast cancer patients receiving docetaxel plus vaccine, and in prostate cancer patients receiving radionuclide plus vaccine (P = 0.004). Larger randomized studies will be required to validate these findings. These studies, however, provide the rationale for the evaluation of refined immune cell subsets to help determine which patients may benefit most from immunotherapy.
Clinical trials recently completed or ongoing involving LTIB activities:
The major goals of these studies are (a) to conduct science-driven clinical studies of specific immunotherapeutics based on hypothesis-generated preclinical experimentation, and (b) to conduct "proof of concept" clinical studies employing specific immunotherapeutics as part of an immuno-oncology platform. There are four major components to LTIB clinical trials: (a) preclinical studies providing the rationale, (b) preparation of INDs and protocols, etc., and appropriate reviews, (c) the clinical trials, and (d) analyses of patients' immune responses and clinical correlates. Collaborative clinical studies are also ongoing with clinical investigators in the LTIB and in several other Branches of the Center for Cancer Research, NCI, and with clinicians at several extramural Cancer Centers.
- A Phase I, Open-Label, Multiple-Ascending Dose Trial to Investigate the Safety, Tolerability, Pharmacokinetics, Biological and Clinical Activity of Avelumab (MSB0010718C), a Monoclonal anti-PD-L1 Antibody, in Subjects with Metastatic or Locally Advanced Solid Tumors and Expansion to Selected Indications
- First In-Human Phase I Trial of NHS-IL12 in Subjects with Metastatic Solid Tumors
- An Open-Label Phase I Study to Evaluate the Safety and Tolerability of a Modified Vaccinia Ankara (MVA)-based Vaccine Modified to Express Brachyury and T-Cell Costimulatory Molecules (MVA-brachyury-TRICOM)
- A Randomized, Double-Blind, Phase 2 Trial of GI-6301 (Yeast-Brachyury Vaccine) Versus Placebo in Combination with Standard of Care Definitive Radiotherapy in Locally Advanced, Unresectable, Chordoma
- A Phase 2 study of GI-6207 (yeast-CEA vaccine) in Patients with Recurrent Medullary Thyroid Cancer
- A Randomized Phase II Trial Combining Vaccine Therapy with PROSTVAC /TRICOM and Enzalutamide vs. Enzalutamide Alone in Men with Metastatic Castration Resistant Prostate Cancer
- A Phase II Trial of Enzalutamide in Combination with PSA-TRICOM in Patients with Non-metastatic Castration Sensitive Prostate Cancer
- A Randomized, Prospective, Phase II Study to Determine the Efficacy of Bacillus Calmette-Guerin (BCG) given in combination with PANVAC™ versus BCG given alone in Adults with High Grade Non-Muscle Invasive Bladder Cancer (NMIBC) who failed at least 1 Induction Course of BCG.
- A Phase II Study of Neoadjuvant rFowlpox-PSA (L155)-TRICOM (Prostvac-F/TRICOM) in Combination with Vaccinia-PSA (L155)-TRICOM (Prostvac-V/TRICOM) in Men With Prostate Cancer Undergoing Treatment With Radical Prostatectomy
- A Phase I, Open-Label, Multiple-Ascending Dose Trial to Investigate the Safety, Tolerability, Pharmacokinetics, Biological and Clinical Activity of MSB0011359C (TGFβ TRAP) in Subjects with Metastatic or Locally Advanced Solid Tumors with Expansion to Selected Indications
- Phase II Randomized, Placebo-Controlled Trial of PROSTVAC (PSA-TRICOM) in Patients with Clinically Localized Prostate Cancer Undergoing Active Surveillance
- Docetaxel and PROSTVAC for Metastatic Castration Sensitive Prostate Cancer
- Phase I Study of PROSTVAC in Combination with Nivolumab and/or Ipilimumab in Men with PC. PIN study.
- A CV301 Phase 1/1b Study followed by Randomized Phase 2 Study of CV301 in Combination with Nivolumab versus Nivolumab in Subjects with Previously Treated Non-Small Cell Lung Cancer
- A Phase Ib Open Label, Dose Finding Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Avelumab in Combination with M9241 (NHS-IL12) in Subjects with Locally Advanced, Unresectable, or Metastatic Solid Tumors
- A Randomized Phase II trial of Standard of Care Alone or in Combination with Ad-CEA vaccine and Avelumab in Patients with Previously Untreated Metastatic Colorectal Cancer
Recent selected publications:
- Fallon JK…Schlom J, Greiner JW. Enhanced antitumor effects by combining an IL-12/anti-DNA fusion protein with avelumab, an anti-PD-L1 antibody. Oncotarget. 8:20558-71, 2017.
- Donahue RN...Gulley JL, Schlom J. Analyses of the peripheral immunome following multiple administrations of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody. J ImmunoTher Cancer 5:20, 2017.
- Heery CR…Schlom J, Gulley JL. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. Published online. 3/31/17.
- Fujii R…Schlom J, Hodge JW. A potential therapy for chordoma via antibody-dependent cell-mediated cytotoxicity (ADCC) employing NK or high affinity NK (haNK) cells in combination with cetuximab. J. Neurosurg (in press).
- Jochems C...Schlom J. An NK cell line (haNK) expressing high levels of granzyme and engineered to express the high affinity CD16 allele. Oncotarget 7:86359-73, 2016.
- Farsaci B… Gulley JL, Schlom J. Analyses of pre-therapy peripheral immunoscore and response to vaccine therapy. Cancer Immunol Res. 4:755-65, 2016.
- Vandeveer AJ…Schlom J. Systemic immunotherapy of non–muscle invasive mouse bladder cancer with avelumab, an anti–PD-L1 immune checkpoint inhibitor. Cancer Immunol Res. 4:452-62, 2016.
- Kim PS…Schlom J. IL-15 superagonist/IL-15RαSushi-Fc fusion complex (IL-15SA/IL-15RαSu-Fc; ALT-803) markedly enhances specific subpopulations of NK and memory CD8+ T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas. Oncotarget. 7:16130-45, 2016.
Farsaci B, Donahue RN, Grenga I, Lepone LM, Kim PS, Dempsey B, Siebert JC, Ibrahim NK, Madan RA, Heery CR, Gulley JL, Schlom J. Analyses of Pretherapy Peripheral Immunoscore and Response to Vaccine Therapy. Cancer Immunol Res. 2016;4(9):755-65.
Boyerinas B, Jochems C, Fantini M, Heery CR, Gulley JL, Tsang KY, Schlom J. Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells. Cancer Immunol Res. 2015;3(10):1148-1157.
Heery CR, Singh BH, Rauckhorst M, Marté JL, Donahue RN, Grenga I, Rodell TC, Dahut W, Arlen PM, Madan RA, Schlom J, Gulley JL. Phase I Trial of a Yeast-Based Therapeutic Cancer Vaccine (GI-6301) Targeting the Transcription Factor Brachyury. Cancer Immunol Res. 2015;3(11):1248-56.
Jochems C, Tucker JA, Tsang KY, Madan RA, Dahut WL, Liewehr DJ, Steinberg SM, Gulley JL, Schlom J. A combination trial of vaccine plus ipilimumab in metastatic castration-resistant prostate cancer patients: immune correlates. Cancer Immunol Immunother. 2014;63(4):407-18.
Hodge JW, Grosenbach DW, Aarts WM, Poole DJ, Schlom J. Vaccine therapy of established tumors in the absence of autoimmunity. Clin Cancer Res. 2003;9(5):1837-49.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
This page was last updated on June 15th, 2017