Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT03369353 |
| Other study ID # |
P00030890 |
| Secondary ID |
|
| Status |
Enrolling by invitation |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
May 1, 2017 |
| Est. completion date |
January 2030 |
Study information
| Verified date |
October 2023 |
| Source |
Boston Children's Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The goal of the Precision Diagnosis in Inflammatory Bowel Disease, Cellular Therapies, and
Transplantation (PREDICT) trial is to apply a systems-biology approach to enable precision
diagnostics for the key immunologic outcomes for patients with Inflammatory Bowel Disease,
Cellular Therapeutics and Transplantation. This approach will deepen the understanding of the
molecular mechanisms driving auto- and allo-immune diseases and serve as a critical platform
upon which to design evidence-based treatment paradigms for these patients.
This research study will examine the immunology of auto- and allo-immune gastrointestinal
disturbances such as Inflammatory Bowel Disease (IBD), Graft-versus-Host Disease (GVHD), and
Functional Gastrointestinal Disorder (FGID), as well as the immune manifestations after CAR-T
and other cellular therapeutics. The Investigators seek to use blood and tissue samples in
order to better understand the mechanisms driving these diseases and their therapies.
The Investigators further hypothesize that longitudinal systems-based immunologic analysis
will enable the patient-specific determination of the molecular evolution of IBD, GVHD and
the response to cellular therapeutics, as well post-transplant defects in protective
immunity, and determine which pathways, when perturbed, can cause clinical disease. The
discovery of these pathways will lead to improved diagnostic, prognostic and treatment
approaches, and to personalized therapeutic decision-making for these patients.
Description:
Hypotheses:
Hypothesis #1: The Investigators hypothesize that they can define the molecular mechanisms
responsible for Inflammatory Bowel Disease (IBD) and gastrointestinal (GI) acute GVHD and
differentiate it from other inflammatory disorders by using advanced immunologic analysis
including flow cytometry, TCR deep sequencing and transcriptomics.
Hypothesis #2: The Investigators further hypothesize that longitudinal systems-based
immunologic analysis will enable the patient-specific determination of the molecular
evolution of IBD as well as acute and chronic GVHD as well post-transplant defects in
protective immunity, and determine which pathways, when perturbed, can cause clinical
disease. The discovery of these pathways will lead to improved diagnostic, prognostic and
treatment approaches, and to personalized therapeutic decision-making for patients undergoing
hematopoietic stem cell transplantation (HCT).
Hypothesis #3: We hypothesize that we can define the molecular mechanisms, phenotypic and
functional immunologic characteristics involved in distinct determinants of adoptive cellular
therapies, including the efficacy, longevity and toxicity associated with cellular therapy.
Longitudinal characterization of cellular therapeutics and the endogenous immune response
they elicit using advanced immunologic analysis including flow cytometry, mass spectrometry,
TCR deep sequencing and single-cell transcriptomics will allow identification and distinction
of pathways critical for efficacy and toxicity and enable subsequent therapeutic modulation.
Hypothesis #4: We hypothesize that differences in the gut microbiome of patients with IBD and
recipients of HCT play a major role in disease severity and overall clinical outcomes in both
diseases (e.g. bacteremia, unexplained fevers, mortality). The longitudinal characterization
of the gut microbial communities by next generation sequencing will allow for detection of
sequential microbial changes that coincide with observed clinical changes. the discovery of
significant changes in the microbiome that are repeatedly observed with a particular clinical
outcome will lead to better mechanistic understanding of its pathophysiology and inform
future diagnostic and preventive approaches.
Hypothesis #5: We hypothesize that immune dysregulation associated with a wide range of
disorders will alter the immune response to vaccines, compounding susceptibility to
infectious diseases in these populations. Specifically, HCT and solid organ transplant
recipients, as well as patients with active or recent history of malignancy, or autoimmune
diseases may have reduced T and B cell responses to SARS-CoV-2 vaccination due to the effect
of disease pathophysiology or treatment regimens on immune function. Comprehensive serologic
analysis, high parameter flow cytometry, and T and B cell RNA sequencing will enable
longitudinal analysis of neutralizing antibody titers and antigen-specific T and B cell
expansion, phenotype, diversity, and survival following vaccination in these patient
populations, as well as in related and unrelated healthy controls. These data will provide
mechanistic insight into how immune impairment in these disorders contributes to poor
responses to infections. as SARS-CoV-2 is a pathogen to which much of the population remains
naïve, this represents a unique opportunity to study the immune response to a novel challenge
in immunocompromised individuals. Moreover, these findings will inform public health
guidelines on how to improve measures to protect vulnerable populations from preventable
disease.
Aims:
Specific Aim #1: To identify the mechanisms specific for IBD and GI acute GVHD and delineate
it from other inflammatory disorders.
Objective 1: Perform flow cytometry, TCR deep sequencing and whole transcriptome analysis on
T cells purified from GI tissue samples taken from patients who undergo endoscopy for
presumed GI GVHD, inflammatory bowel disease (IBD), and functional gastrointestinal disease
(FGID).
Objective 2: Perform flow cytometry, TCR deep sequencing and transcriptome analysis on T
cells from the peripheral blood at the time of endoscopy in patients diagnosed with GI GVHD,
IBD, and FGID.
Specific Aim #2: Characterize the immunologic dysregulation responsible for IBD, acute GVHD,
chronic GVHD and defects in protective immunity in patients undergoing HCT.
Objective 1: Perform longitudinal immune analysis on T cells and B cells purified from
patients with IBD and those undergoing allogeneic HCT. For transplant patients, we will
compare T and B cell immunity in patients who develop acute and chronic GVHD, relapse, and
infectious complications post-transplant and compare to patients without these complications.
Objective 2: Perform microbiome analysis longitudinally in patients with IBD and those
undergoing HCT to determine the impact of microbiome alterations in the development of
post-transplant complications.
Specific Aim #3: Identify the molecular and cellular immunologic mechanisms involved in
determining the clinical response to cellular therapies and distinguish pathways critical to
a successful anti-tumor response from those involved in adverse effects.
Objective 1: Characterize the cellular product prior to administration and track its
distribution, kinetics, persistence and function longitudinally in vivo in the patient's
peripheral blood and when applicable bone marrow, CSF and other tissues, using qPCR-based
transgene detection (if applicable), flow cytometry, mass cytometry, TCR deep sequencing and
whole transcriptome analysis on T cells and other immune cells contained in the cellular
product.
Objective 2: Longitudinally interrogate the interplay of the cellular therapy with the
endogenous immune system and delineate the role of the endogenous immune response in the
efficacy, persistence and toxicity of cellular therapy, using flow cytometry, mass cytometry,
TCR deep sequencing, whole transcriptome analysis on endogenous immune cells and analysis of
soluble factors and antibodies.
Specific Aim #4:Characterize the antigen-specific adaptive immune response to SARS-CoV-2
vaccination in patients with immune dysregulation due to cancer, transplantation, or
autoimmune disease and identify mechanisms underlying impaired generation of durable
immunity.
Objective 1: Perform comprehensive longitudinal analysis of serologic immunity pre- and
post-vaccination, including to booster vaccines, in patients and healthy controls, including
assessment of SARS-CoV-2 specific antibody levels and neutralizing antibody titers.
Objective 2: Use high parameter flow cytometry, single cell RNA sequencing (scRNAseq), and T
and B cell repertoire analysis to characterize the longitudinal development of
antigen-specific T and B cell memory to SARS-CoV-2 following vaccination and subsequent
booster vaccines in patients and healthy controls.
Objective 3: Assess the ability of sera and cloned antibodies from patients to respond to
bind and neutralize viral variants, as compared to that of healthy controls.
Background and Significance:
IBD: Inflammatory bowel disease (IBD) which includes Crohn's Disease (CD) and Ulcerative
Colitis (UC), is a chronic complex gastrointestinal (GI) autoimmune condition that inflicts
1.4 million people in the united states1. The incidence and prevalence of both CD and UC are
increasing over time and encompassing larger areas of the world1,2. In addition, pediatric
IBD comprises 25% of all diagnosed IBD, relegating the child to a lifetime of
gastrointestinal disease and exposure to immunosuppression especially during a period meant
for growth and development. Despite ongoing research into the pathogenesis and genetic
abnormalities, the mechanism behind IBD development and progression is not well understood.
Standard therapies still rely on steroids, other non-specific immunosuppression (such as
methotrexate and azathioprine), and anti-TNF biologics. Although newer therapies such as
agents that block cytokines and leukocyte trafficking are emerging, no universally successful
treatments have been identified. Thus, relapsing forms of IBD continue to lead to systemic
compromise in nutritional absorptive capacity, anemia, and often, to the need for surgical
interventions. Deciphering the mechanisms driving the unique subtypes of IBD (even within UC
and CD) then optimizing treatment based on the underlying systemic dysregulation is a
critical unmet need in the field. While the underlying immune mechanism of IBD remains
undetermined, there is significant data to suggest that IBD may represent an inappropriate
immune response towards self antigens and commensal microbiota in a genetically susceptible
host3. Thus, murine colitis models suggest that mucosal inflammation results from pathologic
T helper- (Th) cell responses, along with regulatory cell defects. These data have emerged
from experiments in IL-2 deficient mice4, IL-10 deficient mice5, TGF-beta6, and TGF-betaGRII
dominant negative transgenic mice7. The pathogenesis also includes an exaggeration in
effector cell responses, which have emerged from experiments in Stat4 transgenic mice8 and
TNFARE mutant mice9. More recently human cytokine analysis suggests that despite clinical
similarities, each subtype of IBD show distinctive cytokine profiles10. Although initial
studies have begun to target specific effector T cell pathways11, the application of target
organ transcriptomics is in its infancy and individual targetable pathways are still elusive.
HCT: Allogeneic HCT is an effective treatment for patients with malignant and non-malignant
hematologic diseases. However, this treatment is complicated with high rates of morbidity and
mortality limiting its broader application. The leading causes of post-transplant morbidity
and mortality include acute and chronic GVHD, relapse and infectious disease. The goal of the
PREDICT trial is to apply a systems approach to understanding the mechanisms driving these
complications, such that evidence-based treatment strategies can be devised.
Acute GVHD: Acute GVHD is mediated by donor-derived allo-reactive T cells becoming activated
and resulting in cytotoxicity against host cells12,13 as well as cytokine-mediated tissue
damage. Moderate to severe acute GVHD can occur in up to 60% of patients undergoing HCT and
the more severe forms have been associated with mortality rates >50%14-17. The most common
sites of the immune-mediated tissue damage are the liver, skin, and gastrointestinal (GI)
tract. GI GVHD occurs in 40-50% of HCT patients and is the major cause of morbidity and
mortality from this disease17.
The diagnosis of GI GVHD is derived from clinical and histopathological findings. GVHD can
occur in both the upper and lower GI tract leading to symptoms of diarrhea, abdominal pain,
nausea, vomiting, and/or anorexia12. Histopathological diagnostic criteria for GI GVHD
includes identification of crypt cell apoptosis, crypt destruction and/or mucosa
denudation18. Unfortunately, the severity of GVHD on histology is poorly correlated with the
clinical course of the disease.
While GI GVHD is a common complication following HCT there remain many barriers to its
consistent and accurate diagnosis. First, diagnosis is dependent on appropriate tissue
sampling. Visible lesions are frequently absent19 and endoscopic findings can be diffuse and
nonspecific. There is also no consensus on the optimal location of the GI tract for biopsies
or number of biopsies needed to secure a diagnosis. There is also frequent discordance
between biopsy specimens from the upper and lower GI tract20. Second, patients presenting
early in the course of GVHD may have subtle histopathological findings that may be missed or
not yet present. At the onset of GVHD few apoptotic cells may be seen and crypt loss and
mucosal damage may yet to have occured18. Lastly, there are also confounding factors that can
lead to the misdiagnosis of GVHD that include conditioning regimen related toxicity,
concomitant infections, and medications which can all cause focal inflammation of the GI
tract. In the first 20 days following a myeloablative conditioning regimen diffuse apoptosis
can be seen mimicking acute GVHD21. Clostridium difficile and cytomegalovirus infections can
also have similar clinical and histopathological presentations22. Use of mycophenolate
mofetil23 and proton pump inhibitors24 have also been found associated with GI tract
apoptosis that can be misdiagnosed as GVHD. All of these factors lead to the high degree of
inter-observer variability in the histological diagnosis of GVHD18,25 and poor correlation
with the clinical observations, illustrating the need for more sensitive and specific methods
of diagnosis.
There have been recent advances in the identification of biomarkers in GVHD that have
diagnostic and prognostic significance. IL-8, IL-2 receptor-alpha, tumor necrosis factor
receptor-1 (TNF-1), hepatocyte growth factor (HGF), elafin, regenerating islet-derived
3-alpha (reg-3alpha), TIM3, IL-6, ST2, B-cell activating factor (BAFF), IL-33, CXCL10, and
CXCL11 have all been found to have utility in predicting the development of GVHD26-28. While
these biomarkers have been identified they have not been extensively validated and are yet to
be clinically adopted as a guide to alter treatment. Moreover, the biomarkers discovered thus
far are often the result of downstream pathway perturbations and discovering the upstream
dysregulation that occurs earlier in the course of the disease may be valuable in developing
diagnostic or prognostic models that could lead to trials aimed at altering the natural
course of the disease.
Our group has previously shown that by using advanced immunologic analysis including flow
cytometry, and whole transcriptome analysis, we can identify previously unrecognized
molecular pathways active in GVHD29-31. We anticipate that by utilizing a systems immunology
approach in patients with acute GVHD we will be able to identify pathways that have
diagnostic and prognostic value. This may enhance our diagnostic capacity and most
importantly, allow us to individualize management of patients based on their specific
immunologic profiles.
Chronic GVHD: CGVHD occurs in 40-60% of transplant patients32-35 with the incidence of this
disease rising in the past 2 decades36 chronic GVHD causes significant mortality, and in
those patients that survive, it can result in profound effects on quality of life37-40.
Despite the increased frequency of chronic GVHD, accurate diagnosis and evidence-based
therapy is still lacking. Thus, while chronic GVHD biomarkers have been identified there have
yet to be any that qualify for clinical application41. Moreover, these biomarkers often
represent end-stage pathway perturbations and may result from nonspecific inflammation and
tissue damage as well as counter-regulatory mechanisms. In addition to the challenges in
diagnosis, there are significant treatment challenges as well: Thus, treatment of chronic
GVHD has not changed significantly over the past few decades. First line therapy remains
corticosteroids with or without calcineurin inhibitiors (CNIs)42-44 and unfortunately,
approximately 50% of patients will fail and require second line treatment45,46 with
failure-free survival at 2 years following second-line therapy being only 25%47. These data
underscore the significant unmet needs in this field, both for molecular diagnostics and
evidence-based treatment paradigms.
Protective Immunity: In addition to the challenges of acute and chronic GVHD, patients
undergoing HCT and those with IBD face other toxicities as well, many of which are related to
dysfunctional immune reconstitution after transplant. However, although the phenomenology of
the many defects in protective immunity (both against infectious pathogens and against
leukemia relapse) is well-documented, the causative molecular mechanisms remain unknown. To
address these questions, our group and others have begun to perform detailed assessments of
immunologic reconstitution after HCT including the application of new T Cell Receptor (TCR)
and B cell Receptor (BCR) deep-sequencing technologies30,48-54. These technologies allow the
investigation of the breadth and depth of post-transplant immune reconstitution at a level of
molecular detail not previously possible and hold the promise of deepening our understanding
of the impact of infectious pathogens on global immune health and immune reconstitution. The
widespread application of these technologies, and their intersection with detailed assessment
of immune phenotype and function can provide novel insights about the state of immune health
in transplant patients, and holds the promise of identifying patients in need of novel
interventions to improve their post-transplant immune reconstitution.
The goal of the PREDICT trial is to apply a systems-biology approach to enable precision
diagnostics for the key immunologic outcomes post-transplant. This approach will deepen our
understanding of the molecular mechanisms driving the most deadly post-transplant
complications, and serve as a critical platform upon which to design evidence-based treatment
paradigms for transplant patients.
Cellular Therapy: Novel adoptive cell therapies are increasingly entering clinical trials and
are available as FDA approved biologics, thereby providing a therapeutic option for
previously refractory patients. This broad and exciting field includes chimeric-antigen
receptor (CAR) T cells directed against a variety of antigens55, T cells genetically modified
to express TCRs56,57, cytokine-stimulated NK-cells58, as well as tumor vaccine approaches
with endogenous, irradiated tumor samples59 or immune cells pulsed with tumor antigen.60
Chimeric antigen-receptor T cells have led to dramatic responses, particularly in patients
with CD19+ B-cell malignancies61-64, leading to FDA approval of several products. While
unprecedented clinical remissions can be achieved initially, the approach is frequently
limited by the durability of the response and CAR T cell persistence with an EFS of 50% at 12
months after infusion61, tumor escape mechanisms65 and significant toxicity involving
cytokine release syndrome, neurologic toxicity66. In the context of CAR T cell therapy, key
factors for successful application have been identified and include incorporation of a
costimulatory signaling mechanism67,68, association of in vivo CAR T cell expansion with
response69 and contribution of T cell phenotypic subgroups with capacity to proliferate and
persist long term70. Additionally, important insights into the roles of IL-6 and IL-1 in
cytokine release syndrome and neurotoxicity71,72 and the contribution of a pan-T cell
infiltrate and high cytokine levels in the CNS as mediators of neurotoxicity 73, have been
gained by our group and others. However, there is a significant unmet need to apply a
systematic approach interrogating the determinants of a successful response, toxicity,
interaction with the endogenous immune system and short- and long-term effects of
interventions aimed at reducing toxicity such as administration of the IL6R-antagonist
Tocilizumab or IL-1 blockade74.
In this study we aim to systematically interrogate the characteristics of cell therapy
products, evolution after administration in vivo and behavior in different compartments such
as peripheral blood, bone marrow, CNS and if applicable tissues and their interplay with the
endogenous immune system. Single cell transcriptomics, coupled with TCR-sequencing (when
applicable BCR sequencing) and phenotypic characterization of transferred and endogenous
immune cells as well as analysis of secreted immune factors such as cytokines, chemokines and
antibodies in the plasma will be employed and correlated with clinical responses. This
unbiased, systematic precision-diagnostic approach will allow identification of critical
pathways which are common or distinct depending on the nature of the cell therapeutic
approach, target and disease entities and associated or segregable from undesired toxicities.
This will critically inform future rational design of cellular therapeutics and inform
possible therapeutic interventions after cell therapy administration.
Vaccine Responses: A common theme among stem cell and solid organ transplant recipients,
patients with current or prior malignancy, and patients with autoimmune or rheumatologic
disease, including IBD, is impaired immune regulation, which is often compounded by the
effect of immune-modifying treatments, including radiation, chemotherapy, and long-term
immunosuppression. 15% of solid organ transplant recipients are hospitalized with a
vaccine-preventable illness in the first five years after transplant in spite of measures to
immunize these patients (Feldman et al., 2019), which is consistent with studies showing
impaired responses to vaccines in these patients (Madan et al., 2008; Mazzone et al., 2004).
HCT recipients respond to variable degrees to vaccination, but do not mount the same
magnitude of response as in healthy controls, and may have further altered responses if they
also have GVHD (Avetisyan et al., 2008; Shalabi et al., 2019). Patients with rheumatologic or
autoimmune disease have also been shown to have impaired responses to particular vaccines,
especially if on immunomodulatory agents such as TNFalpha blockade (Dell' Era et al., 2011).
Studies of childhood cancer survivors suggest that immune impairment may persist beyond
disease resolution; pediatric leukemia survivors who do not receive HCT have impaired humoral
and adaptive immunity at treatment completion(Perkins et al., 2017; Top et al., 2020), and
some patients do not respond, and others may have waning immunity(Nilsson et al., 2002; Top
et al., 2020) in spite of re-vaccination attempts. As immunization efforts against SARS-CoV-2
become widespread, insight on the vaccine response in immunocompromised patients will be
critical to informing more effective strategies to protect this population from severe
COVID-19, which can be extrapolated to other vaccine-preventable pathogens.
In this study we propose to use a systematic approach to longitudinally profile humoral and
antigen-specific T and B cell responses following SARS-CoV-2 vaccination in patients with a
broad range of immune-modifying diseases. Blood samples from patients will be collected prior
to, and at regular intervals following, vaccination. We will assess the durability and
magnitude of long-term antibody responses using isotype-specific ELISAs and neutralizing
antibody assays. High-parameter flow cytometry and scRNAseq will enable high-resolution
phenotyping of antigen-specific T and B cell memory cells, as well as repertoire analysis,
which may impact the likelihood of immune escape in vaccinated patients. Finally, this study
will allow us to determine whether cloned antibodies or serum from patients with immune
dysregulation are less able to neutralize viral variants, providing insight on whether
reduced clonal diversity in patients may result in less protection against viral variants.
