First-in-human phase I study of HPN424, a tri-specific half-life extended PSMA-targeting T-cell engager in patients with metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5552-5552
Author(s):  
Johanna C. Bendell ◽  
Lawrence Fong ◽  
Mark N. Stein ◽  
Tomasz M. Beer ◽  
Ashley Ross ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Half Life ◽  
Cell Activation ◽  
Geometric Mean ◽  
Life Extension ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Binding Domains ◽  
Bone Scans

5552 Background: HPN424 is a first-in-class, prostate-specific membrane antigen (PSMA)-targeting T-cell engager designed as a small, globular protein to enable efficient solid-tumor penetration with prolonged half-life. HPN424 is derived from the TriTAC platform (Tri-specific T-Cell-Activating Construct) and engineered with three binding domains: anti-PSMA for tumor cell engagement, anti-albumin for half-life extension and anti-CD3 for T-cell engagement. Methods: This Ph I study is evaluating HPN424 in progressing mCRPC patients (pts) who have received >2 prior systemic therapies. Primary endpoints are safety, tolerability and determination of MTD/RP2D. Secondary objectives are pharmacokinetics (PK), pharmacodynamics, immunogenicity, and preliminary anti-tumor activity. HPN424 is administered IV once weekly. Tumor assessments include PSA, CT, and bone scans every 9 weeks. Results: As of 1/17/20, 27 pts were dosed in 8 cohorts ranging from 1.3 to 72ng/kg. Pts received a median of 6 prior systemic regimens, including >1 novel AR therapy, and 59% received prior chemotherapy for mCRPC. Median PSA at baseline was 251 ng/mL (range: 0.05 – 5000). No DLTs have been observed. The most common grade >3 TRAEs were cytokine release syndrome (CRS) (3 pts) and transient elevated liver transaminases (2 pts) that occurred concurrently with CRS. All CRS events resolved and pts were successfully re-treated. Short-term steroid premedication was effective in limiting CRS and allowing long-term weekly treatment. HPN424 demonstrated dose proportional increase in Cmax and AUC with a geometric mean T1/2 of 30.5 hours. Dose-dependent, transient increases in peripheral cytokine and chemokine levels were observed. Reduction in circulating tumor cells (CTCs) was seen in 11 of 19 pts with measurable CTC at baseline. Six pts had PSA decreases from baseline ranging from -3.8% to -76%, including 2 pts with PSA decline ≥50%. Ten of 20 pts (50%) with > 18 weeks follow-up remained on study beyond week 18 and includes 8 pts on study > 24 weeks. Conclusions: HPN424 represents a novel half-life extended PSMA-targeting T-cell engager that can be safely administered once weekly. AEs have been transient and manageable. Cytokine increases indicate T-cell activation. CTC reductions in subset of pts suggest target engagement. Early signs of clinical activity include PSA reductions and time on study, including 8 pts on study > 24 weeks. Dose escalation is ongoing, including exploration of step dosing. Clinical trial information: NCT03577028 .

scholarly journals Phase Ib study of patients with metastatic castrate-resistant prostate cancer treated with different sequencing regimens of atezolizumab and sipuleucel-T

2021 ◽  
Vol 9 (8) ◽  
pp. e002931
Author(s):  
Tanya Dorff ◽  
Yosuke Hirasawa ◽  
Jared Acoba ◽  
Ian Pagano ◽  
David Tamura ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Vaccine ◽  
Objective Response ◽  
Specific Antigen ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Sequential Administration

BackgroundCombining an immune checkpoint inhibitor with a tumor vaccine may modulate the immune system to leverage complementary mechanisms of action that lead to sustained T-cell activation and a potent prolonged immunotherapeutic response in metastatic castration resistant prostate cancer (mCRPC).MethodsSubjects with asymptomatic or minimally symptomatic mCRPC were randomly assigned in a 1:1 ratio to receive either atezolizumab followed by sipuleucel-T (Arm 1) or sipuleucel-T followed by atezolizumab (Arm 2). The primary endpoint was safety, while secondary endpoints included preliminary clinical activity such as objective tumor response and systemic immune responses that could identify key molecular and immunological changes associated with sequential administration of atezolizumab and sipuleucel-T.ResultsA total of 37 subjects were enrolled. The median age was 75.0 years, median prostate specific antigen (PSA) was 21.9 ng/mL, and subjects had a median number of three prior treatments. Most subjects (83.8%) had at least one treatment-related adverse event. There were no grade 4 or 5 toxicities attributed to either study drug. Immune-related adverse events and infusion reactions occurred in 13.5% of subjects, and all of which were grade 1 or 2. Of 23 subjects with Response Evaluation Criteria in Solid Tumors measurable disease, only one subject in Arm 2 had a partial response (PR) and four subjects overall had stable disease (SD) at 6 months reflecting an objective response rate of 4.3% and a disease control rate of 21.7%. T-cell receptor diversity was higher in subjects with a response, including SD. Immune response to three novel putative antigens (SIK3, KDM1A/LSD1, and PIK3R6) appeared to increase with treatment.ConclusionsOverall, regardless of the order in which they were administered, the combination of atezolizumab with sipuleucel-T appears to be safe and well tolerated with a comparable safety profile to each agent administered as monotherapy. Correlative immune studies may suggest the combination to be beneficial; however, further studies are needed.Trial registration numberNCT03024216.

scholarly journals Programmable half-life and anti-tumour effects of bispecific T-cell engager-albumin fusions with tuned FcRn affinity

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Ole A. Mandrup ◽  
Sui Ching Ong ◽  
Simon Lykkemark ◽  
Anders Dinesen ◽  
Imke Rudnik-Jansen ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Half Life ◽  
Cell Activation ◽  
Human Albumin ◽  
Life Extension ◽  
Egfr Expression ◽  
Double Transgenic Mouse ◽  
Bispecific T Cell Engager

AbstractFc-less bispecific T-cell engagers have reached the immuno-oncology market but necessitate continual infusion due to rapid clearance from the circulation. This work introduces a programmable serum half-life extension platform based on fusion of human albumin sequences engineered with either null (NB), wild type (WT) or high binding (HB) FcRn affinity combined with a bispecific T-cell engager. We demonstrate in a humanised FcRn/albumin double transgenic mouse model (AlbuMus) the ability to tune half-life based on the albumin sequence fused with a BiTE-like bispecific (anti-EGFR nanobody x anti-CD3 scFv) light T-cell engager (LiTE) construct [(t½ 0.6 h (Fc-less LiTE), t½ 19 hours (Albu-LiTE-NB), t½ 26 hours (Albu-LiTE-WT), t½ 37 hours (Albu-LiTE-HB)]. We show in vitro cognate target engagement, T-cell activation and discrimination in cellular cytotoxicity dependent on EGFR expression levels. Furthermore, greater growth inhibition of EGFR-positive BRAF mutated tumours was measured following a single dose of Albu-LiTE-HB construct compared to the Fc-less LiTE format and a full-length anti-EGFR monoclonal antibody in a new AlbuMus RAG1 knockout model introduced in this work. Programmable half-life extension facilitated by this albumin platform potentially offers long-lasting effects, better patient compliance and a method to tailor pharmacokinetics to maximise therapeutic efficacy and safety of immuno-oncology targeted biologics.

398 AGEN1181, an Fc engineered anti-CTLA-4 antibody, demonstrates clinical activity, alone or in combination with balstilimab (anti-PD-1), and broadens the therapeutic potential of CTLA-4 therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A423-A423
Author(s):  
Steven O’Day ◽  
Anthony El khoueiry ◽  
Chethan Ramamurthy ◽  
Andrea Bullock ◽  
Irina Shapiro ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Models ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Control ◽  
Clinical Activity ◽  
Small Subset ◽  
Tumor Bearing Mouse ◽  
High Affinity ◽  
Tumor Bearing

BackgroundImmune checkpoint therapies targeting CTLA-4, alone, or in combination with anti-PD-1 have shown durable responses in cancer patients. However, responses are limited to a small subset of patients in the most common immunogenic cancers. Here we describe, a novel anti-CTLA-4 antibody, AGEN1181, with enhanced FcyR-dependent functionality that harnesses a novel mechanism of action to promote superior T cell activation and anti-cancer immunity. Concordant with preclinical findings, we report preliminary safety, pharmacodynamic and efficacy data from a phase 1 study of AGEN1181 (NCT03860272), alone or in combination with balstilimab (anti-PD-1 antibody) in a range of immunogenic and non-immunogenic tumors.MethodsThe functional activity of AGEN1181 or AGEN1181-like mouse surrogate were assessed in primary cell-based assays or in PD-1 refractory syngeneic tumor-bearing mouse models (B16F10 or KPC pancreatic tumor). Efficacy was evaluated as monotherapy, or in combination with anti-PD-1, focal radiation or chemotherapy. In an ongoing phase I study, AGEN1181 is administered intravenously once every 3- or 6-weeks as monotherapy (0.1–4 mg/kg), or every 6-weeks (1–4 mg/kg) in combination with balstilimab (3 mg/kg) dosed every 2 weeks. Dose-limiting toxicities were evaluated in the first 28 days of treatment. Neoantigen burden was assessed from pre-treatment tumor biopsy, as available, by next-generation sequencing. Fcγ receptor genotyping was assessed by real-time PCR. Immunophenotyping of peripheral blood mononuclear cells collected pre- and post-treatment were analyzed by flow cytometry.ResultsPreclinically, AGEN1181 demonstrated superior T cell activation than a standard IgG1 anti-CTLA-4 analogue in donors expressing either the low or high affinity FcγRIIIA. In poorly immunogenic tumor-bearing mouse models, AGEN1181-like surrogate demonstrated robust tumor control in combination with anti-PD-1 and focal radiation or chemotherapy. As of August 25th, 2020, we observed a clinical benefit rate of 63–53% at 6 and 12 weeks respectively among evaluable treated patients. We observed two durable responses in patients with endometrial cancer that were BRCA-, microsatellite stable and PD-L1 negative. These patients progressed on prior PD-1 therapy or chemoradiation respectively. Notably, responders expressed either the low or high affinity FcγRIIIA. AGEN1181 showed potent dose-dependent increases in peripheral CD4+Ki67+, CD4+ICOS+ and CD4+HLA-DR+ T-cells. Treatment was well tolerated through the highest dose tested. Grade 3 or greater immune-related adverse events occurred in 28.5% patients and were consistent with CTLA-4 therapies.ConclusionsAGEN1181 is designed to expand the benefit of anti-CTLA-4 therapy to a broader patient population. AGEN1181, alone or in combination with balstilimab, demonstrates clinical activity in heavily pretreated patients.Trial RegistrationNCT03860272

406 CDX527–01, a phase 1 dose-escalation and expansion study of the PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A431-A431
Author(s):  
Michael Yellin ◽  
Tracey Rawls ◽  
Diane Young ◽  
Philip Golden ◽  
Laura Vitale ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Clinical Studies ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Clinical Activity ◽  
Tumor Types ◽  
Anti Tumor Activity

BackgroundCD27 ligation and PD-1 blockade elicit complementary signals mediating T cell activation and effector function. CD27 is constitutively expressed on most mature T cells and the interaction with its ligand, CD70, plays key roles in T cell costimulation leading to activation, proliferation, enhanced survival, maturation of effector capacity, and memory. The PD-1/PD-L1 pathway plays key roles in inhibiting T cell responses. Pre-clinical studies demonstrate synergy in T cell activation and anti-tumor activity when combining a CD27 agonist antibody with PD-(L)1 blockade, and clinical studies have confirmed the feasibility of this combination by demonstrating safety and biological and clinical activity. CDX-527 is a novel human bispecific antibody containing a neutralizing, high affinity IgG1k PD-L1 mAb (9H9) and the single chain Fv fragment (scFv) of an agonist anti-CD27 mAb (2B3) genetically attached to the C-terminus of each heavy chain, thereby making CDX-527 bivalent for each target. Pre-clinical studies have demonstrated enhanced T cell activation by CDX-527 and anti-tumor activity of a surrogate bispecific compared to individual mAb combinations, and together with the IND-enabling studies support the advancement of CDX-527 into the clinic.MethodsA Phase 1 first-in-human, open-label, non-randomized, multi-center, dose-escalation and expansion study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of CDX-527 is ongoing. Eligible patients have advanced solid tumor malignancies and have progressed on standard-of-care therapy. Patients must have no more than one prior anti-PD-1/L1 for tumor types which have anti-PD-1/L1 approved for that indication and no prior anti-PD-1/L1 for tumor types that do not have anti-PD-1/L1 approved for that indication. CDX-527 is administered intravenously once every two weeks with doses ranging from 0.03 mg/kg up to 10.0 mg/kg or until the maximum tolerated dose. The dose-escalation phase initiates with a single patient enrolled in cohort 1. In the absence of a dose limiting toxicity or any ≥ grade 2 treatment related AE, cohort 2 will enroll in a similar manner as cohort 1. Subsequent dose-escalation cohorts will be conducted in 3+3 manner. In the tumor-specific expansion phase, up to 4 individual expansion cohort(s) of patients with specific solid tumors of interest may be enrolled to further characterize the safety, PK, PD, and efficacy of CDX 527. Tumor assessments will be performed every 8-weeks by the investigator in accordance with iRECIST. Biomarker assessments will include characterizing the effects on peripheral blood immune cells and cytokines, and for the expansion cohorts, the impact of CDX-527 on the tumor microenvironment.ResultsN/AConclusionsN/ATrial RegistrationNCT04440943Ethics ApprovalThe study was approved by WIRB for Northside Hospital, approval number 20201542

scholarly journals Association of CD28 IVS3 +17T/C Polymorphism with Soluble CD28 in Rheumatoid Arthritis

2011 ◽  
Vol 30 (1) ◽  
pp. 25-29 ◽  
Author(s):  
I. Y. Ledezma-Lozano ◽  
J. J. Padilla-Martínez ◽  
S. D. Leyva-Torres ◽  
I. Parra-Rojas ◽  
M. G. Ramírez-Dueñas ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
T Cell Activation ◽  
Healthy Subjects ◽  
Cell Activation ◽  
Costimulatory Molecule ◽  
Serum Levels ◽  
Unknown Etiology ◽  
Clinical Activity ◽  
Western Mexico

Objective:Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology in which inflammatory pathology involves T cell activation and the CD28 costimulatory molecule involved in T cell presentation. The gene includes the CD28 IVS3 +17T/C polymorphism that could be associated with susceptibility to RA whereas the soluble concentrations of CD28 (sCD28) could be related to clinical activity.Methods:We investigated the CD28 IVS3 +17T/C polymorphism in 200 RA patients and 200 healthy subjects (HS). Furthermore, we quantified the sCD28 concentrations in 77 samples of each group. We applied indexes focused to determine the activity and disability (DAS28 and Spanish HAQ-DI, respectively) in RA patients.Methods:We investigated the CD28 IVS3 +17T/C polymorphism in 200 RA patients and 200 healthy subjects (HS). Furthermore, we quantified the sCD28 concentrations in 77 samples of each group. We applied indexes focused to determine the activity and disability (DAS28 and Spanish HAQ-DI, respectively) in RA patients.Results:RA patients had significantly higher frequencies of the CD28 T allele compared to HS (p= 0.032 OR = 1.59, C.I. 1.02–2.49). In addition, the IVS3 +17 T/T genotype frequency was also increased in RA vs. HS (p= 0.026). The RA patients showed higher sCD28 serum levels than HS (p= 0.001). Carriers of the T/T genotype in RA patients showed higher sCD28 levels than C/C carriers (p= 0.047). In addition, a correlation between sCD28 and Spanish HAQ-DI (correlation, 0.272;p= 0.016), was found.Conclusion:The T allele in CD28 IVS3 +17T/C polymorphism is associated with a susceptibility to RA in Western Mexico. In addition, increased sCD28 levels are related to T/T genotype in RA patients.

Phase II trial of a GM-CSF-producing and CD40L-expressing cell line combined with allogeneic tumor antigen as a novel vaccine for metastatic lung adenocarcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2559-2559
Author(s):  
Ben C. Creelan ◽  
Scott Antonia ◽  
David Noyes ◽  
Terri B. Hunter ◽  
George R. Simon ◽  
...  
Keyword(s):  
T Cell ◽  
Lung Adenocarcinoma ◽  
Cell Line ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Clinical Activity ◽  
Metastatic Lung ◽  
Grade 3

2559 Background: We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Methods: Intradermal vaccine was given every 14 days x3, followed by monthly x3. Cyclophosphamide (300 mg/m2 IV) was administered before 1st and 4th vaccines to deplete regulatory T-cells. All-trans retinoic acid was given (150/mg/m2/day) after 1st and 4th vaccines to enhance dendritic differentiation. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and after each vaccination. T-cell activation profiles were analyzed by ELISpot assay and tested by generalized Wilcoxon for correlation to survival. Results: 24 participants were accrued at a single center from 10/2006 to 6/2008, with median age 64 and median of 3 previous lines of chemotherapy prior to entry. 20 were former smokers and 4 had brain metastases. A total of 101 vaccines were administered. Common toxicities of any grade were joint pain (79%) and fatigue (75%). Significant adverse events included a grade 3 hypotension and a grade 3 acute respiratory distress. No confirmed complete or partial radiologic responses were observed. Median overall survival (OS) was 8.0 mo (95% CI 3.5 – 12.5) and median time-to-progression was 2.4 mo (95% CI 0.3 – 4.6). Presence of HLA-A2 conferred reduced risk of progression (HR 0.37, 95% CI 0.14 -0.89, p=0.02) and trend to improved OS (HR 0.59, p = 0.06). Of 14 participants with evaluable PBMCs, 5 demonstrated sustained tumor peptide-specific T-cell activation after vaccination. Ex vivo peptide immune response correlated with improved OS compared to non-responders (23 vs. 7 mo, HR 0.48, p = 0.04). Conclusions: Vaccine administration was feasible and tolerable in a heavily pretreated population of metastatic lung cancer. These data suggest the vaccine has clinical activity in the subset with peptide-induced T-cell immune responses and warrants further investigation. A randomized trial of the vaccine is currently in development.

Preclinical evaluation of AMG 160, a next-generation bispecific T cell engager (BiTE) targeting the prostate-specific membrane antigen PSMA for metastatic castration-resistant prostate cancer (mCRPC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 301-301 ◽  
Author(s):  
Julie Bailis ◽  
Petra Deegen ◽  
Oliver Thomas ◽  
Pamela Bogner ◽  
Joachim Wahl ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Half Life ◽  
Cell Activation ◽  
Phase 1 ◽  
Xenograft Model ◽  
Cytokine Release ◽  
Single Chain

301 Background: mCRPC is a disease of high unmet medical need, especially for patients who fail novel hormonal therapies and chemotherapy. BiTE molecules provide an off the shelf therapy that activates a patient’s own immune system and redirects T cells to kill tumor cells. The BiTE mechanism of action is distinct from other immunotherapies and may unlock immune response in mCRPC. PSMA is a compelling BiTE target that is highly expressed on PCa compared to normal tissue and has increased expression in mCRPC. Methods: AMG 160 is a fully human, half-life extended (HLE) BiTE that targets PSMA on tumor cells and CD3 on T cells. AMG 160 comprises two tandem single chain variable fragments fused to an Fc domain. Results: AMG 160 binds human and non-human primate (NHP) PSMA and CD3, leading to T cell activation and proliferation and cytokine production. AMG 160 redirects T cells to kill PSMA-positive cancer cell lines in vitro, including those with low PSMA levels or androgen-independent signaling. Weekly dosing of AMG 160 induces significant antitumor activity in established PCa xenograft model. The pharmacokinetics (PK) and pharmacodynamics of AMG 160 were tested in NHP. AMG 160 treatment led to BiTE target engagement in vivo, including transient T cell activation and cytokine release in blood, and mixed cellular infiltrates in multiple organs known to express PSMA. AMG 160 treatment was well tolerated. Cytokine release associated with the first dose could be attenuated using a step dose regimen. The half-life of AMG 160 in NHP was about one week. Based on allometric scaling, the PK profile of AMG 160 may be projected to enable dosing every other week in humans. Conclusions: AMG 160 is a potent HLE BiTE with specificity for PSMA-positive tumor cells. A Phase 1 study is planned to evaluate the safety and efficacy of AMG 160 in patients with mCRPC.

scholarly journals Light-based tuning of ligand half-life supports kinetic proofreading model of T cell activation

2018 ◽  
Author(s):  
Doug Tischer ◽  
Orion D. Weiner
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ligand Binding ◽  
T Cell Activation ◽  
Half Life ◽  
Cell Activation ◽  
Receptor Occupancy ◽  
Biophysical Parameters ◽  
Ligand Interaction ◽  
Kinetic Proofreading

AbstractT cells are thought to discriminate stimulatory versus non-stimulatory ligands by converting small changes in ligand binding half-life to large changes in cell activation. Such a kinetic proofreading model has been difficult to test directly, as existing methods of altering ligand binding half-life also change other potentially important biophysical parameters, most notably the stability of the receptor-ligand interaction under load. Here we develop an optogenetic approach to specifically tune the binding half-life of a light-responsive ligand to a chimeric antigen receptor without changing other binding parameters. By simultaneously manipulating binding half-life while controlling for receptor occupancy, we find that signaling is strongly gated by ligand binding half-life. Our results provide direct evidence of kinetic proofreading in ligand discrimination by T cells.One Sentence SummaryDirect control of ligand binding half-life with light shows that lifetime, not occupancy, dominates T cell activation.

scholarly journals Optogenetic control shows that kinetic proofreading regulates the activity of the T cell receptor

2018 ◽  
Author(s):  
O. Sascha Yousefi ◽  
Matthias Günther ◽  
Maximilian Hörner ◽  
Julia Chalupsky ◽  
Maximilian Wess ◽  
...  
Keyword(s):  
T Cell ◽  
Ligand Binding ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Half Life ◽  
Cell Activation ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Experimental Systems ◽  
Kinetic Proofreading

AbstractThe pivotal task of the immune system is to distinguish between self and foreign antigens. The kinetic proofreading model (KPR) proposes that T cells discriminate self from foreign ligands by the different ligand binding half-lives to the T cell receptor (TCR). It is challenging to test KPR as the available experimental systems fall short of only altering the binding half-lives and keeping other parameters of the ligand-TCR interaction unchanged. We engineered an optogenetic system using the plant photoreceptor phytochrome B to selectively control the dynamics of ligand binding to the TCR by light. Combining experiments with mathematical modeling we find that the ligand-TCR interaction half-life is the decisive factor for activating downstream TCR signaling, substantiating the KPR hypothesis.One Sentence SummaryThe half-life of the ligand-T cell receptor complex determines T cell activation.

Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy

Blood ◽  
2021 ◽  
Author(s):  
Melissa M Berrien-Elliott ◽  
Michelle Becker-Hapak ◽  
Amanda F. Cashen ◽  
Miriam T. Jacobs ◽  
Pamela Wong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Clinical Activity ◽  
Allogeneic Cell

NK cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from two independent clinical trial cohorts treated with MHC-haploidentical NK cell therapy for relapsed/refractory AML revealed that cytokine support by systemic IL-15 (N-803) resulted in reduced clinical activity, compared to IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T cell numbers in patients treated with IL-15/N-803, compared to IL2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T cell activation and proliferation, compared to IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived ML NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15.

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