scholarly journals 820 Machine learning significantly improves neoantigen-HLA predictions utilizing > 26,000 data points from the PACTImmuneTM Database

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A858-A858
Author(s):  
Vinnu Bhardwaj ◽  
Amin Momin ◽  
Jonathan Johnston ◽  
Elizabeth Speltz ◽  
Tyler Borrman ◽  
...  
Keyword(s):  
Machine Learning ◽  
T Cells ◽  
T Cell ◽  
Test Data ◽  
Characteristic Curve ◽  
Training Data ◽  
Patient Specific ◽  
Cell Capture ◽  
Success Rates ◽  
T Cell Therapy

BackgroundPACT Pharma has developed a state-of-the-art approach to validate predicted neoepitopes (neoEs) and their cognate T cell receptors (neoTCRs) by capturing neoepitope-specific T cells from peripheral blood. This neoTCR discovery and validation process is being applied in clinical trial (NCT03970382) evaluating personalized neoTCR-T cell therapy to treat patients across eight solid tumor types. Extensive pre-, on- and post-treatment data related to this trial has been accumulated in the PACTImmune Database (PIDB) which represents a growing data asset for patient-specific tumor immunogenicity in solid tumors. Here we present a specific use case of applying machine learning (ML) to significantly improve neoE-HLA predictions and further model anticipated improvements of TCR capture as a direct consequence.MethodsPACT has developed capabilities for high-throughput manufacturing of single polypeptide (comPACT protein) which consists of the predicted neoE peptide together with Beta-2-Microglobulin and the HLA heavy chain. comPACT molecules are considered successfully produced when protein yields reach concentrations >1uM. Data used for this study consisted of >26000 neoE-HLA predictions for 62 different HLA alleles. We applied ML to learn patterns that are predictive of neoE-HLAs that can be successfully produced as comPACTs, using scikit-learn and XGBoost. Data was first split into training and testing data. Models were trained on training data and model hyperparameters were tuned using 5-fold cross validation (5xCV). The performance of the models during 5xCV and on test data was measured using the area under the receiver operating characteristic curve (AUC). We additionally performed experimental prospective validation of the models. To do this, 603 neoE-HLAs (from 7 previously unseen cancer samples) were selected for comPACT production using netMHCpan4.1 and the newly trained models.ResultsThe mean AUC for the 5xCV of the selected models ranged from 0.75 to 0.86 depending upon the HLA allele (SD <0.05 for every model). The AUC on the test data ranged from 0.75 to 0.92 (median = 0.85). Prospective validation resulted on average in a 22% higher success rate (range 11%–39%) using the new models as compared to the netMHCpan4.1 predictions. This is expected to result in increased capture of neoepitope-specific CD8+ T cells as the PIDB indicates that 3.2% of the successful comPACTs result in validated neoTCRs.ConclusionsPIDB based ML predictions of neoE-HLAs led to a significant increase in TCR-capturing comPACT success rates. Because of this work, it is predicted both neoE-specific CD8+ T cell capture and actionable neoTCR options will increase per patient.

scholarly journals Needle in a Haystack: The Naïve Repertoire as a Source of T Cell Receptors for Adoptive Therapy with Engineered T Cells

2020 ◽  
Vol 21 (21) ◽  
pp. 8324 ◽  
Author(s):  
Elvira D’Ippolito ◽  
Karolin I. Wagner ◽  
Dirk H Busch
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Receptors ◽  
Adoptive T Cell Therapy ◽  
Patient Specific ◽  
Antigen Specificity ◽  
Adoptive Therapy ◽  
T Cell Therapy ◽  
Cell Receptors

T cell engineering with antigen-specific T cell receptors (TCRs) has allowed the generation of increasingly specific, reliable, and versatile T cell products with near-physiological features. However, a broad applicability of TCR-based therapies in cancer is still limited by the restricted number of TCRs, often also of suboptimal potency, available for clinical use. In addition, targeting of tumor neoantigens with TCR-engineered T cell therapy moves the field towards a highly personalized treatment, as tumor neoantigens derive from somatic mutations and are extremely patient-specific. Therefore, relevant TCRs have to be de novo identified for each patient and within a narrow time window. The naïve repertoire of healthy donors would represent a reliable source due to its huge diverse TCR repertoire, which theoretically entails T cells for any antigen specificity, including tumor neoantigens. As a challenge, antigen-specific naïve T cells are of extremely low frequency and mostly of low functionality, making the identification of highly functional TCRs finding a “needle in a haystack.” In this review, we present the technological advancements achieved in high-throughput mapping of patient-specific neoantigens and corresponding cognate TCRs and how these platforms can be used to interrogate the naïve repertoire for a fast and efficient identification of rare but therapeutically valuable TCRs for personalized adoptive T cell therapy.

scholarly journals Tinkering under the Hood: Metabolic Optimisation of CAR-T Cell Therapy

Antibodies ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 17
Author(s):  
Yasmin Jenkins ◽  
Joanna Zabkiewicz ◽  
Oliver Ottmann ◽  
Nicholas Jones
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Success Rates ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Chimeric antigen receptor (CAR)-T cells are one of the most exciting areas of immunotherapy to date. Clinically available CAR-T cells are used to treat advanced haematological B-cell malignancies with complete remission achieved at around 30–40%. Unfortunately, CAR-T cell success rates are even less impressive when considering a solid tumour. Reasons for this include the paucity of tumour specific targets and greater degree of co-expression on normal tissues. However, there is accumulating evidence that considerable competition for nutrients such as carbohydrates and amino acids within the tumour microenvironment (TME) coupled with immunosuppression result in mitochondrial dysfunction, exhaustion, and subsequent CAR-T cell depletion. In this review, we will examine research avenues being pursued to dissect the various mechanisms contributing to the immunosuppressive TME and outline in vitro strategies currently under investigation that focus on boosting the metabolic program of CAR-T cells as a mechanism to overcome the immunosuppressive TME. Various in vitro and in vivo techniques boost oxidative phosphorylation and mitochondrial fitness in CAR-T cells, resulting in an enhanced central memory T cell compartment and increased anti-tumoural immunity. These include intracellular metabolic enhancers and extracellular in vitro culture optimisation pre-infusion. It is likely that the next generation of CAR-T products will incorporate these elements of metabolic manipulation in CAR-T cell design and manufacture. Given the importance of immunometabolism and T cell function, it is critical that we identify ways to metabolically armour CAR-T cells to overcome the hostile TME and increase clinical efficacy.

scholarly journals Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Laura Castelletti ◽  
Dannel Yeo ◽  
Nico van Zandwijk ◽  
John E. J. Rasko
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Malignant Mesothelioma ◽  
Oncolytic Viruses ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

AbstractMalignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.

scholarly journals HGG-05. REGRESSION OF RECURRENT GLIOBLASTOMA AFTER BORON NEUTRON CAPTURE THERAPY AND CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY IN A CHILD

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii345-iii345
Author(s):  
Hsin-Hung Chen ◽  
Yi-Wei Chen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Boron Neutron Capture Therapy ◽  
Neutron Capture ◽  
Antigen Receptor ◽  
Neutron Capture Therapy ◽  
T Cell Therapy ◽  
Boron Neutron Capture ◽  
Car T

Abstract A 6 y/o girl with recurrent multifocal glioblastoma received 3 times of boron neutron capture therapy (BNCT) and chimeric antigen receptor (CAR)–engineered T cells targeting the tumor-associated antigen HER2. Multiple infusions of CAR T cells were administered over 30 days through intraventricular delivery routes. It was not associated with any toxic effects of grade 3 or higher. After BNCT and CAR T-cell treatment, regression of all existing intracranial lesions were observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid, but new lesions recurred soon after the treatment. This clinical response continued for 14 months after the initiation of first recurrence.

scholarly journals Metabolic and Mitochondrial Functioning in Chimeric Antigen Receptor (CAR)—T Cells

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1229
Author(s):  
Ali Hosseini Rad S. M. ◽  
Joshua Colin Halpin ◽  
Mojtaba Mollaei ◽  
Samuel W. J. Smith Bell ◽  
Nattiya Hirankarn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Metabolic State ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized adoptive cell therapy with impressive therapeutic outcomes of >80% complete remission (CR) rates in some haematological malignancies. Despite this, CAR T cell therapy for the treatment of solid tumours has invariably been unsuccessful in the clinic. Immunosuppressive factors and metabolic stresses in the tumour microenvironment (TME) result in the dysfunction and exhaustion of CAR T cells. A growing body of evidence demonstrates the importance of the mitochondrial and metabolic state of CAR T cells prior to infusion into patients. The different T cell subtypes utilise distinct metabolic pathways to fulfil their energy demands associated with their function. The reprogramming of CAR T cell metabolism is a viable approach to manufacture CAR T cells with superior antitumour functions and increased longevity, whilst also facilitating their adaptation to the nutrient restricted TME. This review discusses the mitochondrial and metabolic state of T cells, and describes the potential of the latest metabolic interventions to maximise CAR T cell efficacy for solid tumours.

98 ATA3271: an armored, next-generation off-the-shelf, allogeneic, mesothelin-CAR T cell therapy for solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A109-A109
Author(s):  
Jiangyue Liu ◽  
Xianhui Chen ◽  
Jason Karlen ◽  
Alfonso Brito ◽  
Tiffany Jheng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Next Generation ◽  
Phase 3 ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cells ◽  
Car T

BackgroundMesothelin (MSLN) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein with high expression levels in an array of malignancies including mesothelioma, ovaria, non-small cell lung cancer, and pancreatic cancers and is an attractive target antigen for immune-based therapies. Early clinical evaluation of autologous MSLN-targeted chimeric antigen receptor (CAR)-T cell therapies for malignant pleural mesothelioma has shown promising acceptable safety1 and have recently evolved with incorporation of next-generation CAR co-stimulatory domains and armoring with intrinsic checkpoint inhibition via expression of a PD-1 dominant negative receptor (PD1DNR).2 Despite the promise that MSLN CAR-T therapies hold, manufacturing and commercial challenges using an autologous approach may prove difficult for widespread application. EBV T cells represent a unique, non-gene edited approach toward an off-the-shelf, allogeneic T cell platform. EBV-specific T cells are currently being evaluated in phase 3 trials [NCT03394365] and, to-date, have demonstrated a favorable safety profile including limited risks for GvHD and cytokine release syndrome.3 4 Clinical proof-of-principle studies for CAR transduced allogeneic EBV T cell therapies have also been associated with acceptable safety and durable response in association with CD19 targeting.5 Here we describe the first preclinical evaluation of ATA3271, a next-generation allogeneic CAR EBV T cell therapy targeting MSLN and incorporating PD1DNR, designed for the treatment of solid tumor indications.MethodsWe generated allogeneic MSLN CAR+ EBV T cells (ATA3271) using retroviral transduction of EBV T cells. ATA3271 includes a novel 1XX CAR signaling domain, previously associated with improved signaling and decreased CAR-mediated exhaustion. It is also armored with PD1DNR to provide intrinsic checkpoint blockade and is designed to retain functional persistence.ResultsIn this study, we characterized ATA3271 both in vitro and in vivo. ATA3271 show stable and proportional CAR and PD1DNR expression. Functional studies show potent antitumor activity of ATA3271 against MSLN-expressing cell lines, including PD-L1-high expressors. In an orthotopic mouse model of pleural mesothelioma, ATA3271 demonstrates potent antitumor activity and significant survival benefit (100% survival exceeding 50 days vs. 25 day median for control), without evident toxicities. ATA3271 maintains persistence and retains central memory phenotype in vivo through end-of-study. Additionally, ATA3271 retains endogenous EBV TCR function and reduced allotoxicity in the context of HLA mismatched targets. ConclusionsOverall, ATA3271 shows potent anti-tumor activity without evidence of allotoxicity, both in vitro and in vivo, suggesting that allogeneic MSLN-CAR-engineered EBV T cells are a promising approach for the treatment of MSLN-positive cancers and warrant further clinical investigation.ReferencesAdusumilli PS, Zauderer MG, Rusch VW, et al. Abstract CT036: A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: Safety and efficacy. Cancer Research 2019;79:CT036-CT036.Kiesgen S, Linot C, Quach HT, et al. Abstract LB-378: Regional delivery of clinical-grade mesothelin-targeted CAR T cells with cell-intrinsic PD-1 checkpoint blockade: Translation to a phase I trial. Cancer Research 2020;80:LB-378-LB-378.Prockop S, Doubrovina E, Suser S, et al. Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation. J Clin Invest 2020;130:733–747.Prockop S, Hiremath M, Ye W, et al. A Multicenter, Open Label, Phase 3 Study of Tabelecleucel for Solid Organ Transplant Subjects with Epstein-Barr Virus-Driven Post-Transplant Lymphoproliferative Disease (EBV+PTLD) after Failure of Rituximab or Rituximab and Chemotherapy. Blood 2019; 134: 5326–5326.Curran KJ, Sauter CS, Kernan NA, et al. Durable remission following ‘Off-the-Shelf’ chimeric antigen receptor (CAR) T-Cells in patients with relapse/refractory (R/R) B-Cell malignancies. Biology of Blood and Marrow Transplantation 2020;26:S89.

scholarly journals A modular and controllable T cell therapy platform for acute myeloid leukemia

Leukemia ◽  
2021 ◽  
Author(s):  
Mohamed-Reda Benmebarek ◽  
Bruno L. Cadilha ◽  
Monika Herrmann ◽  
Stefanie Lesch ◽  
Saskia Schmitt ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Cell Therapy ◽  
Myeloid Leukemia ◽  
Tumor Antigens ◽  
Adoptive T Cell Therapy ◽  
Single Chain ◽  
T Cell Therapy ◽  
Acute Myeloid

AbstractTargeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33+ and CD123+ AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment.

scholarly journals IMMU-31. QUANTITATIVE EVALUATION OF ROUTES OF ADMINISTRATION OF IMMUNOTHERAPEUTIC T CELLS TO ORTHOTOPIC GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii111-ii111
Author(s):  
Lan Hoang-Minh ◽  
Angelie Rivera-Rodriguez ◽  
Fernanda Pohl-Guimarães ◽  
Seth Currlin ◽  
Christina Von Roemeling ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
Adoptive T Cell Therapy ◽  
Whole Body ◽  
T Cell Therapy ◽  
Clinical Responses

Abstract SIGNIFICANCE Adoptive T cell therapy (ACT) has emerged as the most effective treatment against advanced malignant melanoma, eliciting remarkable objective clinical responses in up to 75% of patients with refractory metastatic disease, including within the central nervous system. Immunologic surrogate endpoints correlating with treatment outcome have been identified in these patients, with clinical responses being dependent on the migration of transferred T cells to sites of tumor growth. OBJECTIVE We investigated the biodistribution of intravenously or intraventricularly administered T cells in a murine model of glioblastoma at whole body, organ, and cellular levels. METHODS gp100-specific T cells were isolated from the spleens of pmel DsRed transgenic C57BL/6 mice and injected intravenously or intraventricularly, after in vitro expansion and activation, in murine KR158B-Luc-gp100 glioma-bearing mice. To determine transferred T cell spatial distribution, the brain, lymph nodes, heart, lungs, spleen, liver, and kidneys of mice were processed for 3D imaging using light-sheet and multiphoton imaging. ACT T cell quantification in various organs was performed ex vivo using flow cytometry, 2D optical imaging (IVIS), and magnetic particle imaging (MPI) after ferucarbotran nanoparticle transfection of T cells. T cell biodistribution was also assessed in vivo using MPI. RESULTS Following T cell intravenous injection, the spleen, liver, and lungs accounted for more than 90% of transferred T cells; the proportion of DsRed T cells in the brains was found to be very low, hovering below 1%. In contrast, most ACT T cells persisted in the tumor-bearing brains following intraventricular injections. ACT T cells mostly concentrated at the periphery of tumor masses and in proximity to blood vessels. CONCLUSIONS The success of ACT immunotherapy for brain tumors requires optimization of delivery route, dosing regimen, and enhancement of tumor-specific lymphocyte trafficking and effector functions to achieve maximal penetration and persistence at sites of invasive tumor growth.

158 Inhibition of PI3Kδ improves tumor specific T cell immunity and metabolic fitness

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A172-A172
Author(s):  
Guillermo Rangel Rivera ◽  
Guillermo Rangel RIvera ◽  
Connor Dwyer ◽  
Dimitrios Arhontoulis ◽  
Hannah Knochelmann ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cell Therapy ◽  
Tumor Immunity ◽  
Mitochondrial Function ◽  
T Cell Differentiation ◽  
Tumor Control ◽  
T Cell Therapy

BackgroundDurable responses have been observed with adoptive T cell therapy (ACT) in some patients. However, current protocols used to expand T cells often exhibit suboptimal tumor control. Failure in these therapies has been attributed to premature differentiation and impaired metabolism of the infused T cells. Previous work done in our lab showed that reduced PI3Kδ signaling improved ACT. Because PI3Kγ and PI3Kδ have critical regulatory roles in T cell differentiation and function, we tested whether inhibiting PI3Kγ could recapitulate or synergize PI3Kδ blockade.MethodsTo test this, we primed melanoma specific CD8+ pmel-1 T cells, which are specific to the glycoprotein 100 epitope, in the presence of PI3Kγ (IPI-459), PI3Kδ (CAL101 or TGR-1202) or PI3Kγ/δ (IPI-145) inhibitors following antigen stimulation with hgp100, and then infused them into 5Gy total body irradiated B16F10 tumor bearing mice. We characterized the phenotype of the transferred product by flow cytometry and then assessed their tumor control by measuring the tumor area every other day with clippers. For metabolic assays we utilized the 2-NBDG glucose uptake dye and the real time energy flux analysis by seahorse.ResultsSole inhibition of PI3Kδ or PI3Kγ in vitro promoted greater tumor immunity and survival compared to dual inhibition. To understand how PI3Kδ or PI3Kγ blockade improved T cell therapy, we assessed their phenotype. CAL101 treatment produced more CD62LhiCD44lo T cells compared to IPI-459, while TGR-1202 enriched mostly CD62LhiCD44hi T cells. Because decreased T cell differentiation is associated with mitochondrial metabolism, we focused on CAL101 treated T cells to study their metabolism. We found that CAL101 decreased glucose uptake and increased mitochondrial respiration in vitro, indicating augmented mitochondrial function.ConclusionsThese findings indicate that blocking PI3Kδ is sufficient to mediate lasting tumor immunity of adoptively transferred T cells by preventing premature differentiation and improving mitochondrial fitness. Our data suggest that addition of CAL101 to ACT expansion protocols could greatly improve T cell therapies for solid tumors by preventing T cell differentiation and improving mitochondrial function.

scholarly journals Engineering Next-Generation CAR-T Cells for Better Toxicity Management

2020 ◽  
Vol 21 (22) ◽  
pp. 8620
Author(s):  
Alain E. Andrea ◽  
Andrada Chiron ◽  
Stéphanie Bessoles ◽  
Salima Hacein-Bey-Abina
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Receptors ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Safety Strategies ◽  
Life Threatening ◽  
Preclinical And Clinical Studies

Immunoadoptive therapy with genetically modified T lymphocytes expressing chimeric antigen receptors (CARs) has revolutionized the treatment of patients with hematologic cancers. Although clinical outcomes in B-cell malignancies are impressive, researchers are seeking to enhance the activity, persistence, and also safety of CAR-T cell therapy—notably with a view to mitigating potentially serious or even life-threatening adverse events like on-target/off-tumor toxicity and (in particular) cytokine release syndrome. A variety of safety strategies have been developed by replacing or adding various components (such as OFF- and ON-switch CARs) or by combining multi-antigen-targeting OR-, AND- and NOT-gate CAR-T cells. This research has laid the foundations for a whole new generation of therapeutic CAR-T cells. Here, we review the most promising CAR-T cell safety strategies and the corresponding preclinical and clinical studies.

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