Our Science – Schlom Website
Jeffrey Schlom, Ph.D.
The Laboratory of Tumor Immunology and Biology (LTIB), CCR, is a multidisciplinary and interdisciplinary translational research programmatic effort with the goal of developing novel immunotherapies for cancer. Within this effort are several research groups, a clinical trials group, two independent tenure track investigators, and multiple collaborations with intramural and extramural scientific and clinical investigators, and with investigators in the private sector. The program takes advantage of the uniqueness of the NCI intramural program in that it spans high-risk basic discovery research in immunology, through preclinical translational research, to paradigm-shifting clinical trials. Focus is placed on the design and development of novel 'off-the-shelf' recombinant vaccines 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. The LTIB strategic plan focuses on the development of novel immunotherapeutics for human carcinomas, 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.
Specifically, my research goals consist of four highly integrated projects:
1) The design and development of novel immunotherapeutics consisting of recombinant vector-based vaccines and novel immunomodulators such as checkpoint inhibitors and immunocytokines. This is accomplished in collaboration with Cooperative Research and Development Agreements (CRADA) partners in the private sector that provide agents for preclinical studies in appropriate animal models that we have developed, and in our preclinical human in vitro systems. These studies in turn provide the rationale for science-driven clinical studies.
2) The effect of 'non-immune'‒based therapies on the immune system. Emphasis is placed on the analyses of samples from patients treated with these 'non-immune'‒based therapies. These combined studies provide the scientific rationale for combination clinical trials of immunotherapeutics with standard-of-care therapies or other experimental therapies.
3) Clinical studies of the developed immunotherapeutics as monotherapies or as part of an immuno-oncology platform. Principal Investigators (PIs) and Associate PIs on these trials are Drs. J. Gulley, R. Madan (Genitourinary Malignancies Branch, CCR) and C. Heery, who work closely with me and other LTIB members as a well-integrated immunotherapy team. The 'off-the-shelf' immunotherapeutics that we have developed have also enabled collaborations with clinical investigators at extramural Cancer Centers.
4) The analyses of patients' immune responses post- vs. pre-therapy to identify immune correlates of clinical benefit, and/or to identify those patients most likely to benefit from immunotherapy.
We have continued our preclinical and clinical investigations of two diverse recombinant (rec.) vaccine platforms (each with demonstrated unique properties): (a) rec. poxviral vectors employing a rec. vaccinia prime followed by multiple rec. fowlpox booster vaccinations; each vector contains the transgenes for one or more tumor-associated antigens (TAAs) and three T-cell costimulatory molecules (designated TRICOM); and (b) heat-killed rec. Saccharomyces cerevisiae (yeast) containing TAA protein via the insertion of a yeast plasmid.
We have further interrogated the transcription factor brachyury, which is a major driver of the epithelial-to-mesenchymal transition (EMT) process in human carcinoma cells, as a novel vaccine target. A rec. yeast-brachyury vaccine has been developed and a first-in-human clinical trial is underway.
We have analyzed biopsies of human lung and breast carcinomas and have found overexpression of brachyury mRNA and protein in carcinomas vs. normal adult tissues with the exception of testes and staining in some thyroids. Expression of brachyury has been shown to be increased in higher grade tumors and metastases.
In collaboration with investigators at Duke, we have shown that brachyury expression is significantly and independently associated with a high risk of recurrence and distal metastasis in breast cancer patients treated with tamoxifen.
We have shown that while brachyury is overexpressed in human carcinomas, it is not overexpressed in murine carcinomas. The transcription factor Twist was shown by others to be a driver of the metastatic process in a murine breast carcinoma model. We have demonstrated in murine models that rec. Twist vaccines are capable of mediating anti-tumor therapy directed against an endogenous transcription factor driving the metastatic process.
The C-terminus of MUC1 (MUC1-C) has been shown by others to be an oncogene and is associated with drug resistance and poor prognosis for a range of human tumors. We have now identified 9 novel CD8 T-cell epitopes of MUC1; most importantly, 7 are in the C-terminus. We have identified and characterized enhancer agonist epitopes for each of the 9 epitopes. Rec. vaccines expressing these agonists are being developed.
In collaboration with our CRADA partner, we are characterizing a tumor-targeting immunocytokine. NHS-IL12 is a fully human MAb that binds DNA/histone in necrotic tumor, which is fused to human IL-12 heterodimers. The agent was designed to reduce the toxicity of rec. IL-12 protein while maintaining its immuno-enhancing properties at the tumor site. We have shown that the immunocytokine has anti-tumor activity in a range of tumor models and is extremely effective when used in combination therapies in several models. We have recently initiated a first-in-human clinical trial with NHS-IL12.
We are characterizing, in collaboration with our CRADA partner, an anti-PDL1 MAb that, unlike other anti-PDL1 MAbs, is capable of mediating ADCC of human carcinomas cells. We have initiated a first-in-human clinical trial with this anti-PDL1.
We have analyzed PBMCs from cancer patients both prior to and during standard-of-care therapies to determine whether specific regimens are suitable for use in combination with immunotherapeutics. Breast carcinoma patients undergoing treatment with docetaxel were shown to have some reduction in CD4+ and CD8+ T cells, but the even greater reduction in Tregs during therapy revealed greater eff:Treg ratios.
PBMCs were evaluated from non-small cell lung cancer patients prior to and during cisplatin/vinorelbine therapy. No differences during therapy were seen in CD4+ T cells, but the level of Tregs was decreased, and the suppressive activity of Tregs was decreased in the majority of patients. Similar findings were observed in metastatic prostate cancer patients treated with docetaxel.
Clinical oncologists Drs. Gulley, Madan (Genitourinary Malignancies Branch, CCR) and Heery along with clinical fellows work closely with me and with other members of the LTIB in a well-integrated immunotherapy team.
Prior Phase II studies with rV-, rF-PSA-TRICOM (PROSTVAC) vaccine as a monotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC) have led to an ongoing Phase III study. This is a global 3-arm study in patients (n=1,200) with asymptomatic mCRPC who receive (a) PROSTVAC, (b) PROSTVAC + GM-CSF, (c) placebo (empty vector). The endpoint is overall survival (OS); accrual is expected to be completed in late 2014 or early 2015.
In collaboration with Dr. A. Fojo at the CCR, we have evaluated the growth rates of tumors (via serum PSA) in patients with mCRPC receiving PROSTVAC vaccine or several different chemotherapy regimens. These studies have revealed that, unlike chemotherapy, vaccine therapy can reduce the tumor growth rate leading to enhanced survival even in the absence of increases in PFS. All patients in this trial were evaluated for antibodies to PSA post-vaccination and were negative. Moreover, serum PSA values were in concordance with serum PAP values.
Preclinical LTIB studies showed the superiority of combining intratumoral (i.t.) and systemic (s.c.) vaccination vs. the use of either alone. We have now completed a safety and feasibility study of combined i.t./s.c. PROSTVAC vaccination in men with locally recurrent or progressive prostate cancer. 19/21 patients developed stable or improved PSA levels. A follow-up trial has been initiated to evaluate post- vs. pre-vaccination prostate biopsies following s.c. vaccination only.
Following LTIB preclinical studies, we have completed a Phase I trial in patients with mCRPC of PROSTVAC vaccination with increasing doses of ipilimumab (anti-CTLA4). No adverse events beyond those seen with ipilimumab alone were observed. The OS of patients was quite favorable compared with a similar mCRPC population receiving PROSTVAC alone in a separate trial. Studies by others in patients with metastatic prostate cancer have shown only limited improvement in OS employing ipilimumab alone.
Two randomized studies have recently been completed employing PROSTVAC with standard-of-care therapies. Patients with non-metastatic CRPC received the testosterone-suppressing agent flutamide +/- PROSTVAC. This study provided the rationale for the ongoing trials with enzalutamide plus vaccine. In a second recently accrued trial, patients with mCRPC with bone metastases were randomized to receive the bone-seeking radionuclide Quadramet (Sm-153) +/- PROSTVAC.
A dual center (NCI and MD Anderson) study randomizing patients with metastatic breast cancer to docetaxel +/- PANVAC vaccine (rV-, rF-CEA-MUC1-TRICOM) has recently been completed.
We have completed a first-in-human Phase I study of rec. yeast-CEA vaccine in patients with metastatic disease and demonstrated safety to the generation of CEA-specific T-cell responses. This has led to the initiation of a Phase II study in patients with metastatic medullary thyroid cancer (MTC), where the primary endpoint is tumor growth rate following serum calcitonin, which is a marker for disease progression.
Two randomized clinical studies have recently been initiated employing the novel FDA-approved androgen blockade agent enzalutamide +/- PROSTVAC vaccine. The first is in mCRPC patients with a time-to-progression endpoint; the second trial is in non-metastatic patients with rising PSA where changes in PSA velocity at the discontinuation of enzalutamide will be evaluated.
A clinical study has just opened in collaboration with Dr. P. Agarwal in the CCR Urologic Oncology Branch (UOB). BCG failure bladder cancer patients will be randomized to second-line BCG +/- PANVAC vaccine. The primary endpoint will be tumor extent and immune infiltrate in pre- vs. post-treatment biopsies.
Numerous immune analyses pre- vs. post-treatment have been/are being employed in clinical studies in an attempt to identify which patients would most likely benefit from a given immunotherapy, and to evaluate potential immune correlates of clinical benefit early in the treatment cycle. It is emphasized that any correlations with clinical outcome using any of the immune assays described must be considered only exploratory. True correlations will require the use of validated assays in larger randomized trials.
In addition to the use of the Elispot assay to define CD8+ responses in PBMCs to an immunodominant HLA-A2 epitope, we have now developed a FACS-based assay using 15-mer peptides reflecting entire TAA gene to simultaneously measure both CD4 and CD8 responses; this assay is not restricted by HLA allele.
When sufficient PBMCs were available, we have analyzed the number, phenotype and suppressive function of Tregs and function of NK cells post- vs. pre-vaccination.
We have developed assays to analyze numerous soluble factors in sera pre- and post-immunotherapy. In collaboration with Dr. J. Gildersleeve in the CCR, we have profiled anti-glycan antibodies using glycan arrays in several of our PROSTVAC trials. Pre-vaccination levels of Abs to one specific glycan highly significantly correlated with OS, while no correlations were seen in patients receiving empty vector placebo. Production of antibodies to a second glycan post- vs. pre-vaccination also correlated with overall survival.
We have analyzed post- vs. pre-serum samples for a range of cytokines as well as two potential immunomodulatory molecules. We have shown that soluble CD40L (sCD40L) is elevated in the sera of patients with prostate cancer and metastatic breast and lung cancers. In vitro studies demonstrated sCD40L could enrich MDSC and expand Tregs.
We have shown that soluble CD27 (sCD27) sera levels are decreased in carcinoma patients vs. healthy donors. mCRPC patients treated with PROSTVAC + ipilimumab showed a significant increase in sCD27 post-vaccination, which was associated with increased OS. In vitro studies demonstrated that sCD27 provides strong proliferative signals to lymphocytes.
We have now developed a multi-laser/multi-color FACS-based assay to analyze up to 50 different immune cell subsets in PBMCs pre- vs. post-treatment. In one example, there were associations with OS of several immune cell subsets pre-treatment with PROSTVAC + ipilimumab.
We have used the multi-color FACS-based assay to define a 'peripheral immunoscore' monitoring immune cell subsets known in the literature to have specific immune stimulatory or regulatory functions.
We have now developed the capability, in collaboration with an NCI core facility, to conduct digital immunohistochemistry (IHC) analyses of biopsy specimens. In a trial of i.t./s.c. vaccination with PROSTVAC, there were statistical increases in CD4+ and CD8+ T cells, and decreases in Tregs in post- vs. pre-treatment biopsies. There was an association in best decrease in serum PSA levels and increases in CD8+ TILs post-vaccination. Immunotherapy trials have been initiated or are planned in prostate, bladder, and lung carcinomas in which pre- vs. post-treatment biopsies will be analyzed by digital IHC and compared with changes in specific immune cell subsets in the periphery.
I am involved in the training of numerous postdoctoral and clinical fellows, and medical, college and high school students. I take mentoring very seriously, with frequent meetings with postdoctoral and clinical fellows and with Group Heads. Frequent meetings are held to plan experiments, review and discuss data, and to discuss future plans. Meetings are also held to discuss the preparation of oral presentations, poster presentations, and the writing of manuscripts. All laboratory members attend more formal weekly lab meetings in which planned and ongoing research is discussed. There are also invited seminar speakers, and attendance at the numerous seminars ongoing at the NIH is encouraged.
Two new CRADAs have been established for which I am the PI: one CRADA is with Bavarian Nordic (BN) on the use of rec. poxviral vectors for cancer therapy (non-prostate, non-melanoma, non-hematologic malignancies) and the other is with Merck/EMD-Serono on the therapeutic applications of immune modulators (including anti-PDL1 and the immunocytokine NHS-IL12). This is in addition to two other ongoing CRADAs for which I am the PI: one with BN on rec. poxviral vectors for prostate cancer therapy/prevention, and the other with GlobeImmune for rec. Saccharomyces cerevisiae (yeast) vectors for cancer therapy.
COLLABORATIONS AND TEAM SCIENCE. The translational efforts that other members of the LTIB and I are involved in require both a 'team science' approach and extensive collaborations and interactions with scientific and clinical investigators at (a) other Laboratories/Branches of the CCR, (b) other components of the NIH intramural program and Clinical Center, (c) numerous Cancer Centers throughout the U.S. and abroad, and (d) the private sector. There is a seamless transition from hypothesis-driven preclinical studies to science-based clinical trials. Through numerous Laboratory and informal meetings, clinicians are very much involved in the design of preclinical studies, and scientists are very much involved in the design of clinical studies. This encompasses both 'bench to bedside' and 'bedside to bench' components.
MENTORING. During my career at NCI, I have mentored numerous Postdoctoral Fellows, Clinical Fellows, college, high school and medical studies, and also mentored senior staff members. Many of our former investigators have gone on to successful academic careers and are now Full Professors, Associate Professors, and Directors of Research in academic centers, and several have gone on to high level positions in the private sector.
LIST OF CLINICAL TRIALS
For more information, go to CCR Clinical Trials at NIH website or see 'Links'.
A phase I/II pilot study of sequential vaccinations with rFowlpox-PSA (L155)-TRICOM (PROSTVAC-F/TRICOM) alone, or in combination with rVaccinia-PSA (L155)-TRICOM (PROSTVAC-V/TRICOM), and the role of GM-CSF in patients with prostate cancer [03-C-0176]
A phase I trial of a PSA-based vaccine and an anti-CTLA-4 antibody in patients with metastatic androgen-independent prostate cancer [05-C-0167]
A randomized phase 2.5 Study of 153Sm-EDTMP (Quadramet) with or without a PSA/TRICOM vaccine in men with androgen-insensitive metastatic prostate cancer [07-C-0106]
A phase I feasibility study of an intraprostatic PSA-based vaccine in prostate cancer patients with local failure following radiotherapy or clinical progression on androgen-deprivation therapy in the absence of local definitive therapy [05-C-0017]
An open label pilot study to evaluate the safety and tolerability of PANVAC-V (vaccinia) and PANVAC-F (fowlpox) in combination with sargramostim in adults with metastatic carcinoma [04-C-0246]
Randomized pilot phase II study of docetaxel alone or in combination with PANVAC-V (vaccinia) and PANVAC-F (fowlpox) in adults with metastatic breast cancer [05-C-0229]
An open-label phase I study to evaluate the safety and tolerability of a vaccine (GI-6207) consisting of whole, heat-killed recombinant Saccharomyces cerevisiae (yeast) genetically modified to express CEA protein in adults with metastatic CEA-expressing carcinoma [09-C-0101]
A randomized, double-blind, phase III efficacy trial of PROSTVAC-V/F +/- GM-CSF in men with asymptomatic or minimally symptomatic metastatic, castrate-resistant prostate cancer [11-C-0262]
A randomized phase II trial combining vaccine therapy with PROSTVAC/TRICOM and flutamide vs. flutamide alone in men with androgen insensitive, non-metastatic (D0.5) prostate cancer [07-C-0107]
A randomized phase II trial combining vaccine therapy with PROSTVAC/TRICOM and enzalutamide vs. enzalutamide alone in men with metastatic castration resistant prostate cancer [13-C-0146]
A phase II trial of enzalutamide in combination with PSA-TRICOM in patients with non-metastatic castration sensitive prostate cancer [13-C-0153]
A randomized phase II study of L-BLP25 in combination with standard androgen deprivation therapy and radiation therapy for newly diagnosed, high risk prostate cancer patients [11-C-0247]
A pilot study of recombinant yeast CEA vaccine in patients with recurrent medullary thyroid cancer [13-C-0095]
An open-label phase I study to evaluate the safety and tolerability of GI-6301 a vaccine consisting of whole heat-killed recombinant Saccharomyces cerevisiae (yeast) genetically modified to express Brachyury protein in adults with solid tumors [12-C-0056]
First-in-human phase I trial of NHS-IL12 in subjects with metastatic solid tumors [11-C-0225]
A phase I, open-label, multiple-ascending dose trial to investigate the safety, tolerability, pharmacokinetics, biological and clinical activity of MSB0010718C (anti-PDL1) in subjects with metastatic or locally advanced solid tumors and expansion to selected indications [13-C-0063]
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 [14-C-0036]
Collection of blood, tissue and urine from patients with cancer [02-C-0179]
Follow-up study of subjects previously enrolled in immunotherapy studies utilizing gene transfer or other immunotherapeutic agents [04-C-0274]
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) [pending]
A phase II study of neoadjuvant rFowlpox-PSA (L155)-TRICOM (Prostvac-F/TRICOM) in combination with rVaccinia-PSA (L155)-TRICOM (Prostvac-V/TRICOM) in men with prostate cancer undergoing treatment with radical prostatectomy [pending]
This page was last updated on 4/11/2014.