Peripheral Expansion Research Articles

Early Pharmacodynamic Changes in T-Cell Activation, Proliferation, and Cytokine Production Confirm the Mode of Action of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma

Early Pharmacodynamic Changes in T-Cell Activation, Proliferation, and Cytokine Production Confirm the Mode of Action of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma

CARTITUDE-1: Phase 1b/2 Study of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy, in Relapsed/Refractory Multiple Myeloma

CARTITUDE-1: Phase 1b/2 Study of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy, in Relapsed/Refractory Multiple Myeloma

Single Fraction Stereotactic Body Radiation Therapy Induces Dynamic Changes to the Peripheral Blood T Cell Repertoire in Renal Cell Carcinoma Patients

Clinical studies combining radiation and immunotherapy have shown promising response rates, strengthening efforts to sensitize tumors to immune-mediated attack. Thus, there is an ongoing surge in trials using preconditioning regimens with immunotherapy. Yet, due to scarcity of resected tumors treated in situ with radiotherapy, there has been little investigation of radiation’s sole contributions towards local and systemic anti-tumor immunity in patients. Without this access, translational studies have been limited to evaluating circulating immune subsets and systemic remodeling of peripheral T cell receptor repertoires. This constraint has left gaps in how radiation impacts intratumoral responses and whether tumor-resident T cell clones are amplified following treatment. Therefore, to interrogate the immune impact of radiation on the tumor microenvironment and test the hypothesis that radiation initiates local and systemic expansion of tumor-resident clones, we analyzed renal cell carcinoma from patients treated with stereotactic body radiation therapy. Blood and tumor samples were collected from patients prior to nephrectomy for renal cell carcinoma. These samples were compared to samples from patients treated on a 15 patient clinical trial of single fraction stereotactic body radiation therapy delivered 4 weeks prior to nephrectomy. Transcriptomic comparisons were evaluated by bulk RNA sequencing. T cell receptor sequencing monitored repertoires during the 4-week period between SBRT and nephrectomy. Pathway analysis from tumor transcriptomic data showed radiation-specific enrichment of immune-related processes. T cell receptor sequencing revealed increased clonality in radiation-treated tumors. The frequency of identified, tumor-enriched clonotypes was tracked across serial blood samples. Compared to pre-treatment, we observed increased abundance of tumor-enriched clonotypes 2 weeks post-radiation. However, this expansion was not sustained and contracted towards baseline levels 4 weeks after treatment. Altogether, these results indicate robust intratumoral immune remodeling and a window of tumor-resident T cell expansion following radiation that may be leveraged for rational design of combinatorial strategies. Samples from renal cell carcinoma (RCC) patients underwent high-throughput analysis to reveal transcriptional immune activation and increased clonality in irradiated tumors. Analysis across longitudinal blood samples showed tumor-enriched clonotypes undergo phases of peripheral expansion and contraction following radiation. Collectively, these findings demonstrate radiotherapy remodels intratumoral T cell responses and have significant implications for refined sequencing of combination strategies in RCC.

Antagonism of Macrophage Migration Inhibitory Factory (MIF) after Traumatic Brain Injury Ameliorates Astrocytosis and Peripheral Lymphocyte Activation and Expansion.

Traumatic brain injury (TBI) precedes the onset of epilepsy in up to 15–20% of symptomatic epilepsies and up to 5% of all epilepsy. Treatment of acquired epilepsies, including post-traumatic epilepsy (PTE), presents clinical challenges, including frequent resistance to anti-epileptic therapies. Considering that over 1.6 million Americans present with a TBI each year, PTE is an urgent clinical problem. Neuroinflammation is thought to play a major causative role in many of the post-traumatic syndromes, including PTE. Increasing evidence suggests that neuroinflammation facilitates and potentially contributes to seizure induction and propagation. The inflammatory cytokine, macrophage migration inhibitory factor (MIF), is elevated after TBI and higher levels of MIF correlate with worse post-traumatic outcomes. MIF was recently demonstrated to directly alter the firing dynamics of CA1 pyramidal neurons in the hippocampus, a structure critically involved in many types of seizures. We hypothesized that antagonizing MIF after TBI would be anti-inflammatory, anti-neuroinflammatory and neuroprotective. The results show that administering the MIF antagonist ISO1 at 30 min after TBI prevented astrocytosis but was not neuroprotective in the peri-lesion cortex. The results also show that ISO1 inhibited the TBI-induced increase in γδT cells in the gut, and the percent of B cells infiltrating into the brain. The ISO1 treatment also increased this population of B cells in the spleen. These findings are discussed with an eye towards their therapeutic potential for post-traumatic syndromes, including PTE.

Multiple Subchondral Bone Cysts Cause Deterioration of Articular Cartilage in Medial OA of Knee: A 3D Simulation Study.

AimsTo investigate the impact of subchondral bone cysts (SBCs) in stress-induced osseous and articular variations in cystic and non-cystic knee models using finite element analysis.Materials and Methods3D knee joint models were reconstructed from computed tomography (CT) and magnetic resonance imaging (MRI). Duplicate 3D models were also created with a 3D sphere mimicking SBCs in medial tibia. Models were divided into three groups. In group A, a non-cystic knee model was used, whereas in groups B and C, SBCs of 4 and 12 mm size were simulated, respectively. Cyst groups were further divided into three sub-groups. Each of sub-group 1 was composed of a solitary SBC in the anterior half of tibia adjacent to joint line. In sub-group 2, a solitary cyst was modeled at a lower-joint location, and in sub-group 3, two SBCs were used. All models were vertically loaded with weights representing double- and single-leg stances.ResultsDuring single-leg stance, increase in subchondral bone stress in sub-groups B-1 and B-3 were significant (p = 0.044, p = 0.026). However, in sub-group B-2, a slight increase was observed than non-cystic knee model (9.93 ± 1.94 vs. 9.35 ± 1.85; p = 0.254). All the sub-groups in group C showed significantly increased articular stress (p < 0.001). Conversely, a prominent increase in peri-cystic cancellous bone stress was produced by SBCs in groups B and C (p < 0.001). Mean cartilage shear stress in sub-groups B-1 and B-2 (0.66 ± 0.56, 0.58 ± 0.54) was non-significant (p = 0.374, p = 0.590) as compared to non-cystic model (0.47 ± 0.67). But paired cysts of the same size (B-3) produced a mean stress of 0.98 ± 0.49 in affected cartilage (p = 0.011). Models containing 12 mm SBCs experienced a significant increase in cartilage stress (p = 0.001, p = 0.006, p < 0.001) in sub-groups C-1, C-2, and C-3 (1.25 ± 0.69, 1.01 ± 0.54, and 1.26 ± 0.59), respectively.ConclusionThe presence of large-sized SBCs produced an increased focal stress effect in articular cartilage. Multiple cysts further deteriorate the condition by increased osseous stress effect and high tendency of peripheral cyst expansion in simulated cystic knee models than non-cystic knee models.

‘Protect the Brisbane backyard!’ (Except from subdivision for additional house construction)

ABSTRACT Greyfield infill has been widely pursued as a neoliberally guided consolidation policy favouring high amenity, higher density redevelopments in existing residential areas. In the context of rapidly transforming inner-city suburbs, the question becomes whether consolidation can be achieved through laissez faire zoning combined with strong market incentives for both large- and small-scale developers. This study draws upon an empirical analysis of property boundary change in Brisbane, Australia to demonstrate that without adequate specification, consolidation policy encouraging infill of greyfield inner-city sites can create perverse outcomes that fragment, rather than consolidate, the existing lot structure. The creation of ‘backyard subdivisions’ is one outcome in which additional dwellings are built alongside existing houses protected by preservationist statutes. Despite best intentions to retain dwelling character whilst consolidating growth, redevelopment outcomes do not achieve the purported benefits of consolidation. Clear planning controls are required if greyfield infill is to play a role in halting peripheral urban expansion.

Interleukin 33 Triggers Early Eosinophil-Dependent Events Leading to Metaplasia in a Chronic Model of Gastritis-Prone Mice

Interleukin (IL)33/IL1F11 is an important mediator for the development of type 2 T-helper cell (Th2)-driven inflammatory disorders and has also been implicated in the pathogenesis of gastrointestinal (GI)-related cancers, including gastric carcinoma. We therefore sought to mechanistically determine IL33's potential role as a critical factor linking chronic inflammation and gastric carcinogenesis using gastritis-prone SAMP1/YitFc (SAMP) mice. SAMP and (parental control) AKR mice were assessed for baseline gastritis and progression to metaplasia. Expression/localization of IL33 and its receptor, ST2/IL1R4, were characterized in corpus tissues, and activation and neutralization studies were both performed targeting the IL33/ST2 axis. Dissection of immune pathways leading to metaplasia was evaluated, including eosinophil depletion studies using anti-IL5/anti-CCR3 treatment. Progressive gastritis and, ultimately, intestinalized spasmolytic polypeptide-expressing metaplasia (SPEM) was detected in SAMP stomachs, which was absent in AKR but could be moderately induced with exogenous, recombinant IL33. Robust peripheral (bone marrow) expansion of eosinophils and local recruitment of both eosinophils and IL33-expressing M2 macrophages into corpus tissues were evident in SAMP. Interestingly, IL33 blockade did not affect bone marrow-derived expansion and local infiltration of eosinophils, but markedly decreased M2 macrophages and SPEM features, while eosinophil depletion caused a significant reduction in both local IL33-producing M2 macrophages and SPEM in SAMP. IL33 promotes metaplasia and the sequelae of eosinophil-dependent downstream infiltration of IL33-producing M2 macrophages leading to intestinalized SPEM in SAMP, suggesting that IL33 represents a critical link between chronic gastritis and intestinalizing metaplasia that may serve as a potential therapeutic target for preneoplastic conditions of the GI tract.

Exploring the Pathogenic Role and Therapeutic Implications of Interleukin 2 in Autoimmune Hepatitis.

Interleukin 2 is essential for the expansion of regulatory T cells, and low-dose recombinant interleukin 2 has improved the clinical manifestations of diverse autoimmune diseases in preliminary studies. The goals of this review are to describe the actions of interleukin 2 and its receptor, present preliminary experiences with low-dose interleukin 2 in the treatment of diverse autoimmune diseases, and evaluate its potential as a therapeutic intervention in autoimmune hepatitis. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Interleukin 2 is critical for the thymic selection, peripheral expansion, induction, and survival of regulatory T cells, and it is also a growth factor for activated T cells and natural killer cells. Interleukin 2 activates the signal transducer and activator of transcription 5 after binding with its trimeric receptor on regulatory T cells. Immune suppressor activity is increased; anti-inflammatory interleukin 10 is released; pro-inflammatory interferon-gamma is inhibited; and activation-induced apoptosis of CD8+ T cells is upregulated. Preliminary experiences with cyclic injections of low-dose recombinant interleukin 2 in diverse autoimmune diseases have demonstrated increased numbers of circulating regulatory T cells, preserved regulatory function, improved clinical manifestations, and excellent tolerance. Similar improvements have been recognized in one of two patients with refractory autoimmune hepatitis. In conclusion, interferon 2 has biological actions that favor the immune suppressor functions of regulatory T cells, and low-dose regimens in preliminary studies encourage its rigorous investigation in autoimmune hepatitis.

The Role of TNFR2 and DR3 in the In Vivo Expansion of Tregs in T Cell Depleting Transplantation Regimens.

Regulatory T cells (Tregs) are essential for the maintenance of tolerance to self and non-self through cell-intrinsic and cell-extrinsic mechanisms. Peripheral Tregs survival and clonal expansion largely depend on IL-2 and access to co-stimulatory signals such as CD28. Engagement of tumor necrosis factor receptor (TNFR) superfamily members, in particular TNFR2 and DR3, contribute to promote peripheral Tregs expansion and sustain their survival. This property can be leveraged to enhance tolerance to allogeneic transplants by tipping the balance of Tregs over conventional T cells during the course of immune reconstitution. This is of particular interest in peri-transplant tolerance induction protocols in which T cell depletion is applied to reduce the frequency of alloreactive T cells or in conditioning regimens that allow allogeneic bone marrow transplantation. These conditioning regimens are being implemented to limit long-term side effects of continuous immunosuppression and facilitate the establishment of a state of donor-specific tolerance. Lymphopenia-induced homeostatic proliferation in response to cytoreductive conditioning is a window of opportunity to enhance preferential expansion of Tregs during homeostatic proliferation that can be potentiated by agonist stimulation of TNFR.

CD4+CD28null T cells are expanded in moderately active systemic lupus erythematosus and secrete pro-inflammatory interferon gamma, depending on the Disease Activity Index.

Pathogenic CD4+CD28null cells are characterized by inflammatory cytokine synthesis and tropism to the inflamed tissues. Recent studies showed the involvement of CD28null T cells in a severe clinical outcome of lupus. However, their role in moderately active disease is still unresolved. We examined the levels of circulating CD4+CD28null cells and CD8+CD28null suppressor T cells. We also compared the CD4+CD28null and CD4+CD28+ T-cell functional properties, including the expression of interferon gamma (IFN-γ) and Ki67 among systemic lupus erythematosus (SLE) patients (n = 20) and healthy controls (n = 20). All the patients were under immunosuppressive treatment and exhibited moderate SLE activity (median SLE Disease Activity Index (SLEDAI) = 6). In patients, we found elevated CD4+CD28null and unchanged levels of suppressor CD8+CD28null T cells. There was no difference between patients and controls in IFN-γ and Ki67-expressing CD4+, CD4+CD28+, and CD4+CD28null T cells, except for higher IFN-γ levels in CD4+CD28+ T cells in SLE. In each studied group, we observed a higher preponderance of IFN-γ- and Ki67-expressing cells among CD4+CD28null T cells and lower levels of IFN-γ in CD4+CD28null T cells compared to the CD28+ subset. Similarly, Ki67 intensity was decreased in healthy CD4+CD28null cells, whereas in patients, comparably high expression was observed in both subsets. IFN-γ intensity in CD4+CD28null T cells correlated with SLEDAI. SLE with a moderately active clinical course is characterized by peripheral blood expansion of CD4+CD28null T cells and a normal abundance of suppressor CD8+CD28null T cells. The demonstration that these pathogenic CD4+ T cells, despite the lack of CD28, maintain the ability to produce pro-inflammatory IFN-γ positively correlated with disease activity as well as relatively high proliferative capacity may suggest their potentially predictive role in SLE flares.

Introduction: Evolution of inflammatory arthritis from innate to adaptive immune mechanisms.

Introduction: Evolution of inflammatory arthritis from innate to adaptive immune mechanisms.

Iron complex of a quadruply fused porphyrin: Synthesis, structure and redox properties

An iron(II) complex of a quadruply ring-fused porphyrin (QFP), Fe-1, in which four mesityl groups were introduced at the periphery to improve the solubility in organic solvents, has been newly synthesized and characterized. In the pyridine solution, two pyridine molecules bind to the low-spin Fe[Formula: see text] center of Fe-1 as axial ligands to make the complex stable even under air. Characterization of Fe-1 was performed using 1H NMR spectroscopy, MALDI-TOF-MS spectrometry and single-crystal X-ray diffraction analysis. The 1H NMR signals of Fe-1 were observed in the diamagnetic region, reflecting the low-spin state of the FeII center. In the differential pulse voltammogram of Fe-1, three oxidation waves and four reduction waves were observed in pyridine; the first oxidation wave at -0.08 V vs. Fc/Fc[Formula: see text] can be ascribed to the oxidation process of the FeII center, FeII/FeIII, and other six waves can be assigned to the redox processes of the QFP ligand. Furthermore, the ESR measurement of 1e[Formula: see text]-reduced Fe-1 upon controlled-potential bulk electrolysis in pyridine exhibited a signal at [Formula: see text] = 2.003 with a well-resolved 45-line hyperfine splitting at room temperature, due to the coupling with four nitrogen nuclei and twelve hydrogen ones of the QFP ligand. This indicates that the ligand radical anion of Fe-1 is stabilized by delocalization of the spin density owing to the peripheral ring fusion and resultant expansion of the [Formula: see text]-conjugation.

A theoretical investigation of the effects of metal substituted boron subphthalocyanine chloride on the performance of subPC/C60 organic solar cells

The power conversion efficiency of all-small-organic-molecule solar cells recently has been improved to beyond 12%. Boron subphthalocyanine chloride (subPC), a typical small organic molecule, is frequently used as donor material in photovoltaic devices because of its excellent optical properties and cone-shaped structure. It has been practical to improve the performance of photovoltaic devices based on subPC/C60 through axial, peripheral, and center substitutions or ring expansion of subPC. However, there have been few investigations on the effects of metal substitutions of boron-chloride group on subPC/C60 solar cells. In the present work, we systematically investigate the effects of center metal (Fe, Co, Ni, Cu, and Zn) substitutions on optical and physical properties of subPC/C60 solar cells by using DFT/TDDFT and polarizable continuum model. The outcomes demonstrate that FeSubPC/C60 and CoSubPC/C60 have potential as novel organic solar cells due to their strong photon absorption in the visible region, relatively high open circuit voltage, and low charge transfer state energy. Besides, the bed (C60 on the convex of subPC) configurations of MSubPC/C60 seem to form a new series of donor-acceptor fused molecular materials due to metal-carbon bonding. The work here shows a new way to design photoelectric devices based on subPC.

A theoretical study on electronic spectra of a novel series of metal substituted boron subphthalocyanine chloride.

Boron subphthalocyanine chloride has been extensively studied by experimentalists and computational chemists due to its unique optical and electronic properties. It has been practical to modify the optical and physical properties of subphthalocyanine through axial, peripheral, and center substitutions or ring expansion. However, there have been few investigations on the substitution of central boron atom. In the present work, a new metal-substituted (center substitution of boron atom) series of boron subphthalocyanine chloride (metal=Fe, Co, Ni, Cu, and Zn) are theoretically designed utilizing modern density functional theory. The optimized results of this series in gas phase and with polarizable continuum model show that they may be chemically stable, and the predicted order of the stability of MSubPC is Fe>Cu>Ni>Co>Zn. Also, this new series of MSubPC molecules all becomes more non-planar and has much smaller dipole moments, which imply that they may be feasible for blend with organic acceptors. The HOMO-LUMO energy gaps of MSubPC (M=Co, Ni, Cu) are smaller than that of subPC. Furthermore, the wavelength of simulated absorption peaks of ZnSubPC and NiSubPC is red-shifted with respect to prototype subPC molecule in the visible region, and FeSubPC has noticeably stronger absorption strength than subPC because its excitation involves more orbital transitions and d electrons. The work here shows a new way to design photoelectric materials based on subphthalocyanine with center metal substitution.

Clinical significance of T cell receptor excision circle (TREC) quantitation after allogenic HSCT.

BackgroundHematopoietic stem cell transplantation (HSCT) is a well-established treatment modality for a variety of diseases. Immune reconstitution is an important event that determines outcomes. The immune recovery of T cells relies on peripheral expansion of mature graft cells, followed by differentiation of donor-derived hematopoietic stem cells. The formation of new T cells occurs in the thymus and as a byproduct, T cell receptor excision circles (TRECs) are released. Detection of TRECs by PCR is a reliable method for estimating the amount of newly formed T cells in the circulation and, indirectly, for estimating thymic function. The aim of this study was to determine the role of TREC quantitation in predicting outcomes of human leucocyte antigen (HLA) identical allogenic HSCT.MethodsThe study was conducted on 100 patients receiving allogenic HSCT from an HLA identical sibling. TREC quantification was done by real time PCR using a standard curve.ResultsTREC levels were inversely related to age (P=0.005) and were significantly lower in patients with malignant diseases than in those with benign diseases (P=0.038). TREC levels could predict relapse as an outcome but not graft versus host disease (GvHD) and infections.ConclusionAge and nature of disease determine the TREC levels, which are related to relapse.

First-in-Human, Phase 1/2 Trial to Assess the Safety and Clinical Activity of Subcutaneous GEN3013 (DuoBody®-CD3×CD20) in B-Cell Non-Hodgkin Lymphomas

First-in-Human, Phase 1/2 Trial to Assess the Safety and Clinical Activity of Subcutaneous GEN3013 (DuoBody®-CD3×CD20) in B-Cell Non-Hodgkin Lymphomas

Gab3 adaptor prevents NK cell dysfunction

Immunology Natural killer (NK) cells are innate effector cells that help defend mammals from viral infections and cancer while acting locally in the uterus to support successful pregnancy outcomes. Sliz et al. performed a chemical mutagenesis screen in mice and identified Gab3 as a scaffolding protein required for NK cell priming and peripheral expansion in response to cytokines. Gab3 mutant mice exhibited defects in their ability to control tumors and successfully complete pregnancies because of impaired NK cell function. Thus, an adaptor protein is required to achieve full NK cell function, and subtle uterine NK cell perturbations can contribute to pregnancy failure. Sci. Immunol. 4 , eaav3866 (2019).

Gab3 is required for IL-2– and IL-15–induced NK cell expansion and limits trophoblast invasion during pregnancy

The scaffolding protein Grb2-associated binding protein 3 (Gab3) is a member of the Gab family, whose functions have remained elusive. Here, we identify Gab3 as a key determinant of peripheral NK cell expansion. Loss of Gab3 resulted in impaired IL-2 and IL-15-induced NK cell priming and expansion due to a selective impairment in MAPK signaling but not STAT5 signaling. In vivo, we found that Gab3 is required for recognition and elimination of "missing-self" and tumor targets. Unexpectedly, our studies also revealed that Gab3 plays an important role during pregnancy. Gab3-deficient mice exhibited impaired uterine NK cell expansion associated with abnormal spiral artery remodeling and increased trophoblast invasion in the decidua basalis. This coincided with stillbirth, retained placenta, maternal hemorrhage, and undelivered fetoplacental units at term. Thus, Gab3 is a key component required for cytokine-mediated NK cell priming and expansion that is essential for antitumor responses and limits trophoblast cell invasion during pregnancy.

T cell receptor next-generation sequencing reveals cancer-associated repertoire metrics and reconstitution after chemotherapy in patients with hematological and solid tumors

ABSTRACTThe dynamics of immunoaging and the onset of immunoparesis in healthy individuals and cancer patients has been controversially discussed. Moreover, the role of chemotherapy on T cell regeneration needs further elucidation in light of novel immunotherapies that have become standard of care for many elderly cancer patients. We used next-generation immunosequencing to study T cell receptor (TCR) repertoire metrics on 346 blood samples from healthy individuals and cancer patients producing a dataset with around 8.8 million TCR reads. This analysis showed that decline of T cell diversity and increase in T cell clonality is a continuous process beginning in healthy individuals over 40 years of age. Untreated patients with both hematological and solid tumors showed blood TCR repertoires with significantly lower diversity and higher clonality as compared to healthy individuals across all decades. Loss in T cell diversity was essentially driven by a loss in richness in aging healthy individuals, while in cancer patients a loss in repertoire evenness was an additional contributing factor. Interestingly, chemotherapy did not impair the regeneration of blood TCR repertoire diversity to pre-treatment age-specific levels. Surprisingly, even patients over the age of 70 years receiving highly T cell toxic therapies reestablished their pre-treatment T cell diversity suggesting rebound thymic activity rather than recovery of T cell counts by peripheral expansion only. Taken together, these data suggest that human TCR repertoire metrics gradually deteriorate in the aging individual, but age-specific TCR metrics are restored after T cell depleting therapy even in elderly cancer patients.

Abstract 4100: Receptor occupancy and neo-epitope specific T-cell repertoires in patients with solid tissue tumors following anti-PD-1 therapy

Abstract Background: In patients undergoing chemotherapy and/or immune therapy, endogenous T cells within the tumor micro-environment (TME) and in the periphery are subject to dynamic changes. Particularly, exhausted T cells in the TME and peripheral blood mononuclear cells (PBMCs) isolated from whole blood express the inhibitory receptor, Programmed Cell Death Receptor 1 (PD-1). A small but significant number of these T cells can recognize neo-epitopes (neoE) arising from patient specific mutations. We determined receptor occupancy (RO) in patients treated with monoclonal anti-PD-1 antibody AB122, which is currently in clinical development. Methods: Multi-color flow cytometry was used to determine RO post-AB122 administration using a directly-conjugated competitive antibody to AB122. In addition, we determined RO values using the established method for nivolumab using a biotinylated anti-human IgG4 to detect bound anti-PD-1. The assays were also optimized to determine RO in whole blood from patients with solid tumors treated with AB122. Receptor occupancy using both methods were compared. Further, whole exome sequencing from archival formalin-fixed, paraffin-embedded (FFPE) tissue was performed and T cells that recognized patient-specific neoE resulting from tumor-specific mutations were identified in patient blood. Results: In the dose-escalation study for AB122 monotherapy arm, a variety of dosing regimens have been evaluated, including Q2W, Q3W and Q4W. The number of doses received ranged from 1 to 20. Data from patients in the 80 and 240 mg Q2W cohorts showed that AB122 serum concentrations ≥1.5 μg/mL (equivalent to 10 nM) are associated with full receptor occupancy. The RO associated with AB122 dosing is maintained when dosed in combination with the potent A2aR/A2bR dual adenosine receptor antagonist AB928 in an ongoing clinical trial. Conclusions: Full RO is observed with both cohorts of AB122 monotherapy (80 and 240 mg Q2W) and in the 240 mg Q2W combination with AB928. Study of peripheral target engagement and expansion of neoE-specific T cell populations in a longitudinal study of solid tumor patients treated with AB122 could provide insight towards designing successful combination immune therapy regimens in future clinical trials with AB122. Citation Format: Devika Ashok, Songming Peng, Benjamin Yuen, Matt Walters, Stephen W. Young, Lisa Seitz. Receptor occupancy and neo-epitope specific T-cell repertoires in patients with solid tissue tumors following anti-PD-1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4100.