946 Standardized transcriptional profiling for optimizing cellular therapies: a multi-center PICI-NanoString collaboration

BackgroundThe field of cellular therapy remains one of the most promising areas for the development of new cancer treatments. To further these improvements, it is imperative to broadly understand cell therapy products at the molecular level and to identify factors that contribute to their efficacy. NanoString and the Parker Institute for Cancer Immunotherapy (PICI) have established a ground-breaking collaboration to characterize up to 1,000 apheresis and cellular therapy infusion products with the primary goal to dissect and study molecular pathways that correlate with optimal cellular therapies.MethodsUsing a large and diverse sample cohort collected from eight PICI network Cell Therapy Centers the team will aim to study gene expression profiles (GEP) that correlate with optimal apheresis and downstream cellular products, identifying biomarkers and signatures for clinical response or toxicity and further explore unique cancer-specific and shared characteristics that make an optimal and effective chimeric antigen receptor (CAR) T cell. As shown here, this first of its kind study will include samples that target dozens of different antigens covering both primary and metastatic hematological and solid tumors. Samples will be characterized using the standardized set of genes included in the nCounter CAR-T Characterization Panel and will measure essential components of CAR-T including: metabolic fitness, phenotype, TCR diversity, toxicity, activation, persistence, exhaustion and cell typing along with individual transgene expression.ResultsPresented here are initial questions that will be asked as part of this study. Meta-analysis will be performed as an aggregated set of data and individual site-specific analysis. Data will further be analyzed across individual cancer types, target types, outcome and manufacturing conditions as examples. We anticipate this information will prove useful across many aspects of the development, manufacturing and clinical applications for cellular therapies and further hypothesize that these findings will promote the understanding of pathways affecting safety and efficacy that may help optimize the therapy.ConclusionsThe project is anticipated to begin Fall of 2021 with work continuing in phases through 2022 with periodic data reports to be shared through scientific conferences. All data and findings will be made publicly available to the scientific community through PICI’s Cancer Data and Evidence Library analysis platform (CANDEL).

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Clinical units to set up chimeric antigen receptor T-cell therapy (CAR T-cells): Based on the recommendations of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)

Current Research in Translational Medicine ◽

10.1016/j.retram.2018.04.001 ◽

2018 ◽

Vol 66 (2) ◽

pp. 57-58 ◽

Cited By ~ 7

Author(s):

Ibrahim Yakoub-Agha

Keyword(s):

Bone Marrow ◽

T Cells ◽

Bone Marrow Transplantation ◽

Cell Therapy ◽

Chimeric Antigen Receptor ◽

Cellular Therapy ◽

T Cell Therapy ◽

Car T Cells ◽

Car T ◽

Set Up

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15. Evaluation of Retained Immunity for Tetanus-Diphtheria and Pneumococcal Vaccines in Recipients of Cellular Therapies

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.217 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S131-S132

Author(s):

Georgios Angelidakis ◽

Roy F Chemaly ◽

Partow Kebriaei ◽

Nadim J Ajami ◽

Micah M Bhatti ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Pneumococcal Vaccination ◽

Cell Transplant ◽

Research Support ◽

T Cell Therapy ◽

Hematopoietic Stem ◽

Cellular Therapies ◽

Increased Risk ◽

Car T

Abstract Background Infectious complications in cancer patients (pts) who have received T-cell therapies are similar to those in autologous hematopoietic stem cell transplant (HCT) recipients, who - because they lose prior acquired immunity after undergoing conditioning regimens and transplantation- may be at an increased risk for vaccine-preventable infections. We sought to determine seroprotection rates against pneumococcus and tetanus-diphtheria before and after cellular therapies. Methods In this ongoing prospective observational cohort study, we enrolled pts with any type of cancer who received cellular therapy with chimeric antigen receptor modified T cell (CAR-T), natural killer CAR-T, or T-cell receptor- directed immunotherapies at MD Anderson Cancer Center from January 2020 through May 2021. We performed antibody assays for diphtheria, tetanus, and pneumococcus before, at 1 month, and between 3-6 months after T-cell therapy for each pt regardless of vaccination history. Results Of 38 pts enrolled, 27 (71%) were men and 25 (66%) had non-Hodgkin lymphoma (Table 1); 38 (100%) and 17 (45%) had a history of previous diphtheria-tetanus-acellular pertussis (Tdap) and pneumococcal vaccination, respectively (Table 2). Tetanus serologies were positive for all pts tested before, at 1 month and 3-6 months after T cell therapy (37/37 [100%], 22/22 [100%], and 13/13 [100%], respectively). Diphtheria serologies were positive for most pts tested before, at 1 month and 3-6 months after therapy (35/37 [95%], 20/22 [91%], and 11/13 [85%], respectively]. Pneumococcal serologies were positive for 8 out of 37 [22%] pts before therapy, among these 8 pts, 4 had positive serologies 1 month after therapy, and 2 of 3 tested 3-6 months after therapy had positive serologies. One pt received a pneumococcal vaccine 10 months after therapy but had negative serologies post-vaccination. Conclusion Most pts who received T-cell therapy retained their immunity for diphtheria and tetanus, but most also lost their immunity for pneumococcus. This suggests that the standard of care for pts receiving T-cell therapy should include more robust strategy for pneumococcal vaccination, but its timing, need for booster dosing, and antibody response needs to be determined in future trials. Disclosures Roy F. Chemaly, MD, MPH, FACP, FIDSA, AiCuris (Grant/Research Support)Ansun Biopharma (Consultant, Grant/Research Support)Chimerix (Consultant, Grant/Research Support)Clinigen (Consultant)Genentech (Consultant, Grant/Research Support)Janssen (Consultant, Grant/Research Support)Karius (Grant/Research Support)Merck (Consultant, Grant/Research Support)Molecular Partners (Consultant, Advisor or Review Panel member)Novartis (Grant/Research Support)Oxford Immunotec (Consultant, Grant/Research Support)Partner Therapeutics (Consultant)Pulmotec (Consultant, Grant/Research Support)Shire/Takeda (Consultant, Grant/Research Support)Viracor (Grant/Research Support)Xenex (Grant/Research Support) Fareed Khawaja, MBBS, Eurofins Viracor (Research Grant or Support) Ella Ariza Heredia, MD, Merck (Grant/Research Support)

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Timing and Immune Status after Cellular Therapies Predict Response to COVID-19 Vaccines

Blood ◽

10.1182/blood-2021-151376 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3891-3891

Author(s):

Roni Tamari ◽

Ioannis Politikos ◽

David Knorr ◽

Santosha Vardhana ◽

Jennifer Young ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Cell Count ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Cellular Therapy ◽

Immune Status ◽

Cellular Therapies ◽

Serologic Response ◽

Car T

Abstract BACKGROUND Cellular therapies (allogeneic hematopoietic cell transplantation, allo-HCT, autologous hematopoietic cell transplantation, auto-HCT, and chimeric antigen receptor T cell therapy, CAR T) render patients severely immunocompromised for extended periods post-therapy. Emerging data suggest reduced immune responses to COVID-19 vaccines among patients with hematologic malignancies, but data for cellular therapy recipients are sparse. We therefore assessed immune responses to mRNA COVID-19 vaccines among patients who underwent cellular therapies at our center to identify predictors of response. PATIENT AND METHODS In this observational prospective study, anti-SARS-CoV-2 spike IgG antibody titers and circulating neutralizing antibodies were measured at 1 and 3 months after the 1 st dose of vaccination. CD4, CD19, mitogen, and IgG levels from patient samples collected prior to initiation of vaccination in a subset of patients were used to assess immune recovery and association with response. A concurrent healthy donor (HD) cohort provided control response rates. RESULTS Allo-HCT (N=149), auto HCT (N=61), and CAR T (N=7) patients vaccinated between 12/22/2020- 2/28/2021 with mRNA vaccines and 69 HD participated in this study. At 3 months, 188 pts (87%) had a positive anti-SARS-CoV-2 spike IgG levels (median 5,379 AU/mL, IQR 451-15,750), and 139 (77%) had a positive neutralization Ab assay (median 93%, IQR 36-96%). All HD (100%) had a positive anti-SARS-CoV-2 spike IgG and a positive neutralization Ab assay with median levels of 8,011 AU/mL (IQR 4573-11,159) and 96% (IQR 78- 96%), respectively. Time from vaccination to cellular therapy was associated with response; 67% of patients vaccinated in the first 12 months post-cellular therapy (N=42) mounted a serologic response, compared with patients vaccinated between 12-24 (89%) (N=45), 24-36 (91%) (N=32) and >36 (93%) (N=98) months post-treatment, p= 0.001 (figure 1). Patients with immune parameters below the recommended threshold for vaccinations post-cellular therapies were also less likely to mount a response (figure 2): CD4+ T-cell count < 200 vs >200 cells/μL, 66% vs 87% (p=0.012); CD19+ B-cell count <50 vs >50 cells/μL; 33% vs 95% (p<0.001), phytohemagglutinin mitogen response <40% vs >40%, 42% vs 89% (p<0.001), and IgG <500 vs >500 mg/dl, 71% vs 91% (p=0.003). Patient age, gender, prior COVID-19 infection, treatment with IVIG, and type of mRNA COVID-19 vaccine were not associated with the likelihood of serologic response. CONCLUSION This largest cohort to date, demonstrates that COVID-19 vaccine responses of cellular therapy recipients are reduced compared to healthy control and response varies based on time interval from cellular therapy and immune function at the time of vaccination, underscoring the importance of monitoring immune status parameters, as well as qualitative measures (neutralizing Ab) of vaccine response, in informing clinical decisions, including the indication for booster vaccines. Figure 1 Figure 1. Disclosures Politikos: Merck: Research Funding; ExcellThera, Inc: Other: Member of DSMB - Uncompensated. Vardhana: Immunai: Membership on an entity's Board of Directors or advisory committees. Perales: Equilium: Honoraria; Cidara: Honoraria; Sellas Life Sciences: Honoraria; Miltenyi Biotec: Honoraria, Other; Celgene: Honoraria; MorphoSys: Honoraria; Takeda: Honoraria; Incyte: Honoraria, Other; Karyopharm: Honoraria; Kite/Gilead: Honoraria, Other; Merck: Honoraria; NexImmune: Honoraria; Novartis: Honoraria, Other; Medigene: Honoraria; Omeros: Honoraria; Servier: Honoraria; Bristol-Myers Squibb: Honoraria; Nektar Therapeutics: Honoraria, Other. Shah: Amgen: Research Funding; Janssen Pharmaceutica: Research Funding.

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COVID-19 and hematopoietic stem cell transplantation and immune effector cell therapy: a US cancer center experience

Blood Advances ◽

10.1182/bloodadvances.2020003883 ◽

2021 ◽

Vol 5 (3) ◽

pp. 861-871 ◽

Cited By ~ 2

Author(s):

Katie Maurer ◽

Anna Saucier ◽

Haesook T. Kim ◽

Utkarsh Acharya ◽

Clifton C. Mo ◽

...

Keyword(s):

Stem Cell ◽

Cell Therapy ◽

Hematopoietic Stem Cell ◽

The United States ◽

World Health ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Cellular Therapies ◽

Car T ◽

The Impact

Abstract The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), identified in late 2019 as the causative agent of COVID-19, was declared a pandemic by the World Health Organization on 11 March 2020. Widespread community transmission in the United States triggered a nationwide shutdown, raising major challenges for administration of hematopoietic stem cell transplant (HSCT) and chimeric antigen receptor (CAR)-T cell therapies, leading many centers to delay or cancel operations. We sought to assess the impact of the COVID-19 pandemic on operations and clinical outcomes for HSCT and CAR-T cellular therapies at the Dana-Farber Cancer Institute by reviewing administration and outcomes in 127 cell therapy patients treated during the initial COVID-19 surge: 62 adult allogeneic HSCT (allo-HSCT), 38 autologous HSCT (auto-HSCT), and 27 CAR-T patients. Outcomes were compared with 66 allo-HSCT, 43 auto-HSCT, and 33 CAR-T patients treated prior to the pandemic. A second control cohort was evaluated for HSCT groups to reflect seasonal variation in infections. Although there were changes in donor selection and screening as well as cryopreservation patterns of donor products, no differences were observed across groups in 100-day overall survival, progression-free survival, rates of non–COVID-19 infections, including hospital length of stay, neutrophil engraftment, graft failure, acute graft-versus-host disease in allo-HSCT patients, or cytokine release syndrome and neurotoxicity in CAR-T patients. No HSCT patients contracted COVID-19 between days 0 and 100. One CAR-T patient contracted COVID-19 at day +51 and died of the disease. Altogether, our data indicate that cellular therapies can be safely administered throughout the ongoing COVID-19 pandemic with appropriate safeguards.

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New trends in cellular therapy

Development ◽

10.1242/dev.192567 ◽

2020 ◽

Vol 147 (18) ◽

pp. dev192567 ◽

Cited By ~ 3

Author(s):

Hideyuki Okano ◽

Doug Sipp

Keyword(s):

Stem Cells ◽

Clinical Trials ◽

Cell Therapy ◽

Pluripotent Stem Cells ◽

Clinical Studies ◽

Cellular Therapy ◽

Current Status ◽

Cellular Therapies ◽

Safety Issues ◽

Regenerative Therapies

ABSTRACTRegenerative therapies, including both gene and cellular therapies, aim to induce regeneration of cells, tissues and organs and restore their functions. In this short Spotlight, we summarize the latest advances in cellular therapies using pluripotent stem cells (PSCs), highlighting the current status of clinical trials using induced (i)PSC-derived cells. We also discuss the different cellular products that might be used in clinical studies, and consider safety issues and other challenges in iPSC-based cell therapy.

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Cellular therapies for the treatment of immune-mediated GI and liver disease

British Medical Bulletin ◽

10.1093/bmb/ldaa035 ◽

2020 ◽

Vol 136 (1) ◽

pp. 127-141

Author(s):

Sheeba Khan ◽

Reenam S Khan ◽

Philip N Newsome

Keyword(s):

Clinical Trials ◽

Liver Disease ◽

Cell Therapy ◽

Cellular Therapy ◽

Current Knowledge ◽

Unmet Need ◽

Therapeutic Effects ◽

Cellular Therapies ◽

Gastrointestinal Conditions ◽

Immune Mediated

Abstract Introduction Immune-mediated liver and gastrointestinal diseases are chronic conditions that lack curative treatments. Despite advances in the understanding and treatment of these conditions, they frequently remain refractory to treatment and represent a significant unmet need. Cellular therapies are an emerging option and hold the potential to have a major impact. Data sources A literature review was carried out using Pubmed. Keywords used for search were ‘ATMP’, ‘immune mediated’, ‘autoimmune liver disease’ and ‘immune mediated gastrointestinal conditions’, ‘cell therapy’, ‘MSC’, ‘HSCT’, ‘Regulatory T cells’, ‘GVHD’, ‘Coeliac disease’ ‘IBD’, ‘PSC’, ‘AIH’, ‘PBC’. No new data were generated or analysed in support of this review. Areas of agreement There is substantial evidence from clinical trials to support the use of cell therapies as a treatment for immune-mediated liver and gastrointestinal conditions. Cellular therapy products have the ability to ‘reset’ the dysregulated immune system and this in turn can offer a longer term remission. There are ongoing clinical trials with mesenchymal stromal cells (MSCs) and other cells to evidence their efficacy profile and fill the gaps in current knowledge. Insights gained will inform future trial designs and subsequent therapeutic applications. Areas of controversy There remains some uncertainty around the extrapolation of results from animal studies to clinical trials. Longevity of the therapeutic effects seen after the use of cell therapy needs to be scrutinized further. Heterogeneity in the selection of cells, source, methods of productions and cell administration pose challenges to the interpretation of the data. Growing points MSCs are emerging as a key therapeutic cells in immune-mediated liver and gastrointestinal conditions. Ongoing trials with these cells will provide new insights and a better understanding thus informing future larger scale studies. Areas timely for developing research Larger scale clinical trials to build on the evidence from small studies regarding safety and efficacy of cellular therapy are still needed before cellular therapies can become off the shelf treatments. Alignment of academia and industry to standardize the processes involved in cell selection, manipulation and expansion and subsequent use in clinical trials is an important avenue to explore further.

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