567 MDK1319/MDK-701: A potent fully efficacious peptidyl agonist of IL-7Rαγc, designed with no reference to cytokine or receptor structure and unrelated to IL-7, fused to an Fc-domain for PK enhancement

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A601-A601
Author(s):  
William Dower ◽  
Alice Bakker ◽  
Steven Cwirla ◽  
Prarthana Joshi ◽  
Praechompoo Pongtornpipat ◽  
...  
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Human Lymphocytes ◽  
Receptor Activation ◽  
Biological Properties ◽  
Cross Reactivity ◽  
Lymphocyte Subpopulation ◽  
Minimal Risk

BackgroundIL-7 receptor activation is essential for the proper development and homeostasis of T-cell subpopulations, and maintenance of the TCR clonal repertoire. Emerging evidence indicates potential clinical utility of IL-7 for immunotherapy of lymphopenia, oncology, and other indications. Here we report the discovery of MDK1319, a small novel peptidyl agonist of IL-7R. This peptide is structurally unrelated to IL-7, with a MW less than 5000D. To improve in vivo properties, we fused MDK1319 to an IgG-Fc-domain to construct MDK-701, which exhibits biological properties similar to those of IL-7 in vitro, and when administered to non-human primates.MethodsPeptides were selected from peptide libraries by screens designed to identify molecules binding simultaneously to the Rα and γc subunits of the human IL-7 receptor. Synthetic peptides, and peptides fused to IgG Fc-domains were evaluated for efficacy, potency, and quality of signaling in IL-7-responsive cell lines and human lymphocytes. PK/PD properties in non-human primates were also determined.ResultsMDK1319 and MDK-701 activate the major IL-7R signaling pathways, JAK-STAT (pSTAT5), and PI3K (pAKT), and induce proliferation in human PBMCs, exhibiting lymphocyte subpopulation selectivity, kinetics, efficacy, and potency similar to those of IL-7. Agonism is attributable to direct activation of IL-7R, as shown by dependence on the presence of the IL-7Rα subunit for response in test cells, and insensitivity to IL-7 neutralizing antibodies. MDK1319 and MDK-701 do not activate nor inhibit any other (off target) Rγc family receptors at concentrations 100-fold greater than required for maximal IL-7R activation. MDK-701 administered to cynomologous macaques (single dose, IV at 1 mg/kg) exhibits a circulating terminal half life of ~32 hr; and induces peripheral lymphocyte profiles similar to IL-7 treatment, including initial reduction (tissue migration), followed by sustained elevation of peripheral lymphocytes remaining above baseline for 29 days, with no observed adverse effects.ConclusionsIn addition to the utility of Fc-fusion MDK-701 for monotherapy, the small peptidyl nature of the active peptide MDK1319, fusable to recombinant protein partners, offers opportunities for incorporation into bispecific molecules, linking IL-7 activity to a variety of useful functions. These include synergistic cytokine activities, checkpoint blockade, and tissue targeting. Cells engineered to secrete MDK1319 display autocrine stimulation potentially useful in T-cell therapeutics. The structural novelty of MDK1319 substantially decreases risk of cross reactivity of any anti-drug immune response with endogenous IL-7, and may provide a safer alternative to modified forms of IL-7 reported to produce significant anti-IL-7 immunogenicity.Ethics ApprovalAnimal studies were performed by Envol Biomedical or Charles Rivers Laboratories, as approved by the Institution Ethics Boards with the following study and approval numbers:Envol Biomedical 7037-20 MDK2002; 7037-20: PK/PD Cynomolgus monkeysCharles Rivers Laboratories 20200121001K; US19001: PK Mouse The use of human PBMC in this study was authorized under Minimal Risk Research Related Activities at Stanford Blood Center (SQL 79075)

scholarly journals Optimized Adenovirus-Antibody Complexes Stimulate Strong Cellular and Humoral Immune Responses against an Encoded Antigen in Naïve Mice and Those with Preexisting Immunity

2011 ◽  
Vol 19 (1) ◽  
pp. 84-95 ◽  
Author(s):  
Jin Huk Choi ◽  
Joe Dekker ◽  
Stephen C. Schafer ◽  
Jobby John ◽  
Craig E. Whitfill ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
T Cell Responses ◽  
Transduction Efficiency ◽  
Virus Antibody ◽  
Cell Responses

ABSTRACTThe immune response to recombinant adenoviruses is the most significant impediment to their clinical use for immunization. We test the hypothesis that specific virus-antibody combinations dictate the type of immune response generated against the adenovirus and its transgene cassette under certain physiological conditions while minimizing vector-induced toxicity.In vitroandin vivoassays were used to characterize the transduction efficiency, the T and B cell responses to the encoded transgene, and the toxicity of 1 × 1011adenovirus particles mixed with different concentrations of neutralizing antibodies. Complexes formed at concentrations of 500 to 0.05 times the 50% neutralizing dose (ND50) elicited strong virus- and transgene-specific T cell responses. The 0.05-ND50formulation elicited measurable anti-transgene antibodies that were similar to those of virus alone (P= 0.07). This preparation also elicited very strong transgene-specific memory T cell responses (28.6 ± 5.2% proliferation versus 7.7 ± 1.4% for virus alone). Preexisting immunity significantly reduced all responses elicited by these formulations. Although lower concentrations (0.005 and 0.0005 ND50) of antibody did not improve cellular and humoral responses in naïve animals, they did promote strong cellular (0.005 ND50) and humoral (0.0005 ND50) responses in mice with preexisting immunity. Some virus-antibody complexes may improve the potency of adenovirus-based vaccines in naïve individuals, while others can sway the immune response in those with preexisting immunity. Additional studies with these and other virus-antibody ratios may be useful to predict and model the type of immune responses generated against a transgene in those with different levels of exposure to adenovirus.

scholarly journals T cell memory. Long-term persistence of virus-specific cytotoxic T cells.

1989 ◽  
Vol 169 (6) ◽  
pp. 1993-2005 ◽  
Author(s):  
B D Jamieson ◽  
R Ahmed
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Biological Properties ◽  
Antigenic Specificity ◽  
Ctl Response

This study documents that virus-specific CTL can persist indefinitely in vivo. This was accomplished by transferring Thy-1.1 T cells into Thy-1.2 recipient mice to specifically identify the donor T cell population and to characterize its antigenic specificity and function by using a virus-specific CTL assay. Thy-1.1+ T cells from mice previously immunized with lymphocytic choriomeningitis virus (LCMV) were transferred into Thy-1.2 mice persistently infected with LCMV. The transferred LCMV-specific CTL (Thy-1.1+ CD8+) eliminate virus from the chronically infected carriers and persist in the recipient mice in small numbers, comprising only a minor fraction of the total T cells. Upon re-exposure to virus, these long-lived "resting" CD8+ T cells proliferate in vivo to become the predominant cell population. These donor CD8+ T cells can be recovered up to a year post-transfer and still retain antigenic specificity and biological function. They kill LCMV infected H-2-matched cells in vitro and can eliminate virus upon transfer into a second infected host. In addition, these long-lived CD8+ T cells appear not to be dependent on help from CD4+ T cells, since depletion of CD4+ T cells has minimal or no effect on their biological properties (proliferation, CTL response, viral clearance). These donor CTL also exhibit an immunodominance over the host-derived LCMV-specific CTL response. When both host and donor T cells are present, the donor CTL response is dominant over the potential CTL response of the cured carrier host. Taken together, these results suggest that virus-specific CTL can persist for the life span of the host as memory cells.

scholarly journals Pharmacological and functional similarities of the human neuropeptide Y system in C. elegans challenges phylogenetic views on the FLP/NPR system

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Miron Mikhailowitsch Gershkovich ◽  
Victoria Elisabeth Groß ◽  
Anette Kaiser ◽  
Simone Prömel
Keyword(s):  
Neuropeptide Y ◽  
Pharmacological Study ◽  
Receptor Activation ◽  
Cross Reactivity ◽  
Model Organisms ◽  
Loss Of Function ◽  
C Elegans ◽  
Molecular Studies

Abstract Background The neuropeptide Y system affects various processes, among others food intake, and is frequently discussed in the context of targeting obesity. Studies in model organisms are indispensable to enable molecular studies in a physiological context. Although the NPY system is evolutionarily conserved in all bilaterians, in the widely used model Caenorhabditis elegans there is controversy on the existence of NPY orthologous molecules. While the FMRFamide-like peptide (FLP)/Neuropeptide receptor-Resemblance (NPR) system in the nematode was initially suggested to be orthologous to the mammalian NPY system, later global phylogenetic studies indicate that FLP/NPR is protostome-specific. Methods We performed a comprehensive pharmacological study of the FLP/NPR system in transfected cells in vitro, and tested for functional substitution in C. elegans knockout strains. Further, we phenotypically compared different flp loss-of-function strains. Differences between groups were compared by ANOVA and post-hoc testing (Dunnett, Bonferroni). Results Our pharmacological analysis of the FLP/NPR system including formerly functionally uncharacterized NPY-like peptides from C. elegans demonstrates that G protein-coupling and ligand requirements for receptor activation are similar to the human NPY system. In vitro and in vivo analyses show cross-reactivity of NPY with the FLP/NPR system manifesting in the ability of the human GPCRs to functionally substitute FLP/NPR signaling in vivo. The high pharmacological/functional similarities enabled us to identify C. elegans FLP-14 as a key molecule in avoidance behavior. Conclusions Our data demonstrate the pharmacological and functional similarities of human NPY and C. elegans NPR systems. This adds a novel perspective to current phylogenetic reconstructions of the neuropeptide Y system. NPY and NPR receptors are pharmacologically so similar that the human receptors can functionally compensate for the C. elegans ones, suggesting orthologous relationships. This is also underlined by the presence of NPY-like peptides and parallels in peptide requirements for receptor activation. Further, the results presented here highlight the potential of this knowledge for physiological as well as molecular studies on neuropeptide GPCRs such as the NPY system in the future.

A CD19/CD3 Bispecific Tandab, AFM11, Recruits T Cells To Potently and Safely Kill CD19+ Tumor Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4405-4405
Author(s):  
Eugene Zhukovsky ◽  
Uwe Reusch ◽  
Carmen Burkhardt ◽  
Stefan Knackmuss ◽  
Ivica Fucek ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Cross Reactivity ◽  
Equity Ownership

Abstract To harness the potent tumor-killing capacity of T cells for the treatment of CD19+ malignancies, we developed a humanized bispecific tetravalent antibody, with two binding sites for CD3 and CD19, the CD19/CD3 RECRUIT-TandAb AFM11. CD19 is expressed from early B cell development through differentiation into plasma cells, and is an attractive alternative to CD20 as a target for the development of therapeutic antibodies to treat B cell malignancies such as Non Hodgkin Lymphoma. Since native antibodies cannot recruit T cells, we engineered a bispecific anti-CD19/anti-CD3 TandAb. The tumor-specific CD19 antigen module targets the TandAb to cancer cells, while simultaneously, the CD3 effector module recruits and activates T cells, leading to cancer cell lysis. The advantages of the TandAb technology, relative to other bi-functional fragment antibody scaffolds, include: improved pharmacokinetics (PK) enabling intravenous dosing, more drug-like properties, and avidity-enhanced efficacy for the targeting and killing of tumor cells. We evaluated in vitro efficacy and safety using CD19+ cell lines, and in vivo efficacy in a murine NOD/scid xenograft model reconstituted with human PBMC. Further, we used standard preclinical IND enabling assays to evaluate tissue cross reactivity, PK, and toxicological profile (local tolerance, hematocompatibility, effects on hematopoesis, etc). In vitro assays demonstrated the higher potency and efficacy of target cell lysis by AFM11 relative to a bispecific tandem scFv (that is currently in clinical evaluation). CD8+ T cells dominate early AFM11-mediated cytotoxicity (4 hrs) while after 24 hrs both CD4+ and CD8+ T cells equally contribute to tumor lysis with EC50 between 0.5 – 5 pM; cytotoxicity was independent of CD19 cell-surface density. AFM11 exhibited similar cytotoxicity over effector:target ratios ranging from 5:1 to 1:5, and facilitated serial T cell-killing of its targets. The advantage of AFM11 over the bispecific tandem scFv was most pronounced at lower effector:target ratios. AFM11 activated T cells only in the presence of CD19+ cells. In PBMC cultures, AFM11 induced CD69 and CD25 expression, T cell proliferation, and production of IFN-γ, TNF-α, IL-2, IL-6, and IL-10. Depletion of CD19+ cells from PBMC abrogated these effects, demonstrating that the T cell activation is strictly CD19+ target-dependent. Thus, AFM11 should not elicit the devastating cytokine release observed when full-length antibodies bind CD3. Up to one week co-incubation with AFM11 did not inhibit T cell cytotoxicity, suggesting that the TandAb does not induce anergy. In vivo, AFM11 induced dose-dependent growth inhibition of Raji tumors; a single 0.5 mg/kg dose exhibited efficacy similar to 5 daily injections. In the tissue cross reactivity study, only tissues containing CD19+ and CD3+ cells were stained by AFM11; all other tissues, including vital organs, displayed no cross reactivity. Similarly, no local intolerance was observed in rabbits, and no effect on myeloid and erythroid progenitors was observed in a colony-forming assay. Strong accumulation of 125I-labeled AFM11 was observed in the tumors of mice engrafted with CD19+ cancer cells, and no unspecific organ accumulation was observed. Finally, evaluated on the basis of Cmax and the area under the curve (AUC), AFM11 exhibited dose linearity (20 – 500 mg AFM11 dose range) upon single i.v. bolus administration in mice; half-life (T1/2) ranged from 18.4 to 22.9 hr. In summary, AFM11 is a highly efficacious novel drug candidate for the treatment of CD19+ malignancies with an advantageous safety profile and anticipated dosing regimen. Disclosures: Zhukovsky: Affimed Therapeutics AG: Employment, Equity Ownership. Reusch:Affimed Therapeutics AG: Employment. Burkhardt:Affimed Therapeutics AG: Employment. Knackmuss:Affimed Therapeutics AG: Employment. Fucek:Affimed Therapeutics AG: Employment. Eser:Affimed Therapeutics AG: Employment. McAleese:Affimed Therapeutics AG: Employment. Ellwanger:Affimed Therapeutics AG: Employment. Little:Affimed Therapeutics AG: Consultancy, Equity Ownership.

scholarly journals An affinity-matured human monoclonal antibody targeting fusion loop epitope of dengue virus with in vivo therapeutic potency

2020 ◽  
Author(s):  
Tomohiro Kotaki ◽  
Takeshi Kurosu ◽  
Ariadna Grinyo ◽  
Edgar Davidson ◽  
Siti Churrotin ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Human Monoclonal Antibody ◽  
Variable Region ◽  
Cross Reactivity ◽  
Affinity Maturation ◽  
Interferon Α ◽  
Fusion Loop

AbstractDengue virus (DENV), from the genus flavivirus of the family flaviviridae, causes serious health problems globally. Human monoclonal antibodies (HuMAb) can be used to elucidate the mechanisms of neutralization and antibody-dependent enhancement (ADE) of DENV infections, leading to the development of a vaccine or therapeutic antibodies. Here, we generated eight HuMAb clones from an Indonesian patient infected with DENV. These HuMAbs exhibited the typical characteristics of weak neutralizing antibodies including high cross-reactivity with other flaviviruses and targeting of the fusion loop epitope (FLE). However, one of the HuMAbs, 3G9, exhibited strong neutralization ability (NT50 < 0.1 µg/ml) and possessed a high somatic hyper-mutation rate of the variable region, indicating affinity-maturation. Administration of this antibody significantly improved the survival rate of interferon-α/β/γ receptor knockout C57BL/6 mice after a lethal DENV challenge. Additionally, Fc-modified 3G9 molecules that had lost their in vitro ADE activity showed significantly enhanced therapeutic potency in vivo and competed strongly with an ADE-prone antibody in vitro. Taken together, the affinity-matured FLE-targeting antibody 3G9 exhibits several promising features for therapeutic application including a low NT50 value, potential for pan-flavivirus infection treatment, and suppression of ADE. This study demonstrates the therapeutic potency of affinity-matured FLE-targeting antibodies.

scholarly journals Differential major histocompatibility complex-related activation of idiotypic suppressor T cells. Suppressor T cells cross-reactive to two distantly related lysozymes are not induced by one of them.

1980 ◽  
Vol 152 (3) ◽  
pp. 521-531 ◽  
Author(s):  
L Adorini ◽  
M A Harvey ◽  
D Rozycka-Jackson ◽  
A Miller ◽  
E E Sercarz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Cross Reactivity ◽  
Suppressor T Cells ◽  
Cell Repertoire ◽  
Helper Cells

B10 (H-2b) mice are genetic nonresponders to hen egg-white lysozyme (HEL) and the distantly related human lysozyme (HUL). However, anti-HEL or anti-HUL primary antibody responses in vivo or in vitro can be obtained in B10 mice by immunization with the appropriate lysozyme coupled to erythrocytes. T cells able to suppress either anti-lysozyme plaque-forming cells (PFC) response are induced in B10 mice after immunization with HEL-complete Freund's adjuvant (CFA) or HUL-CFA. This cross-reactivity of HEL and HUL in the induction and the expression of suppressive activity is in marked contrast to their very low cross-reactivity at the PFC level. These results suggest that either HEL or HUL can stimulate a suppressor T cell which recognizes a particular epitope present on both lysozymes. Suppressor cells induced by HEL or HUL bear the same predominant idiotype found on the majority of anti-HEL antibodies, and on the small proportion of anti-HUL antibodies cross-reactive with HEL. B10.Q (H-2q) mice are responders in vivo to HEL-CFA, but not to HUL-CFA. In contrast to B10, HEL-CFA priming in B10.Q micr induces helper cells whereas HUL-CFA priming induces suppressor cells. These suppressor cells are cross-reactive with HEL and are fully able to suppress HEL-specific helper cells. The presence of HEL-specific suppressor cell precursors in B10.Q mice which are not activated by HEL, seems to implicate differential choice by the antigen presenting system as a basis for Ir gene control, rather than the absence of a regulatory cell type from the T cell repertoire.

scholarly journals An affinity-matured human monoclonal antibody targeting fusion loop epitope of dengue virus with in vivo therapeutic potency

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tomohiro Kotaki ◽  
Takeshi Kurosu ◽  
Ariadna Grinyo-Escuer ◽  
Edgar Davidson ◽  
Siti Churrotin ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Human Monoclonal Antibody ◽  
Variable Region ◽  
Cross Reactivity ◽  
Affinity Maturation ◽  
Interferon Α ◽  
Fusion Loop

AbstractDengue virus (DENV), from the genus flavivirus of the family flaviviridae, causes serious health problems globally. Human monoclonal antibodies (HuMAb) can be used to elucidate the mechanisms of neutralization and antibody-dependent enhancement (ADE) of DENV infections, leading to the development of a vaccine or therapeutic antibodies. Here, we generated eight HuMAb clones from an Indonesian patient infected with DENV. These HuMAbs exhibited the typical characteristics of weak neutralizing antibodies including high cross-reactivity with other flaviviruses and targeting of the fusion loop epitope (FLE). However, one of the HuMAbs, 3G9, exhibited strong neutralization (NT50 < 0.1 μg/ml) and possessed a high somatic hyper-mutation rate of the variable region, indicating affinity-maturation. Administration of this antibody significantly prolonged the survival of interferon-α/β/γ receptor knockout C57BL/6 mice after a lethal DENV challenge. Additionally, Fc-modified 3G9 that had lost their in vitro ADE activity showed enhanced therapeutic potency in vivo and competed strongly with an ADE-prone antibody in vitro. Taken together, the affinity-matured FLE-targeting antibody 3G9 exhibits promising features for therapeutic application including a low NT50 value, potential for treatment of various kinds of mosquito-borne flavivirus infection, and suppression of ADE. This study demonstrates the therapeutic potency of affinity-matured FLE-targeting antibodies.

566 MDK-202: An empirically-designed peptidyl agonist of the IL-2/15βγc receptor, devoid of Rα interaction, unrelated to IL-2 or IL-15, and fused to an Fc-domain for PK enhancement

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A600-A600
Author(s):  
William Dower ◽  
Steven Cwirla ◽  
Blake Williams ◽  
Praechompoo Pongtornpipat ◽  
Prarthana Joshi ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Ex Vivo ◽  
Human Lymphocytes ◽  
In Vivo Studies ◽  
Attractive Alternative ◽  
Minimal Risk ◽  
Duration Of Action ◽  
Recombinant Peptide ◽  
Human Pbmc

BackgroundEfforts to modify IL-2 for immuno-oncology applications focus on modifying the receptor selectivity of IL-2 to bias effects on immune cells; in particular, to reduce Rα interaction via mutation, chemical modification, complexation with antibodies, or fusion to the Rα-ectodomain. IL-2/15Rβγc-biased agonists also incorporate PK enhancement to extend duration of action, and reduce side effects associated with peak drug levels. We previously reported discovery of small synthetic peptides, unrelated to IL-2 or IL-15, that simultaneously bind IL-2Rβ and γc subunits to induce IL-2/15R signaling. These peptides do not bind IL-2Rα, and are therefore IL-2/15Rβγc-selective agonists with MW less than 5000D. We now describe properties of an IL-2/15Rβγc agonist peptide fused to an Fc-domain (MDK-202).MethodsPeptides were selected from recombinant peptide libraries to identify molecules binding simultaneously to the β and γc subunits of IL-2/15R. Active peptides were fused to Fc-domains to evaluate efficacy, potency, and quality of signaling upon activating IL-2/15Rβγc in cell lines and human lymphocytes. PK and PD properties in mice and NHP were also determined.ResultsMDK-202 exhibits in vitro potency similar to the synthetic peptide (MDK1169). MDK-202 does not bind IL-2Rα, activates the major IL-2/15R signaling pathways: JAK-STAT(pSTAT5), MAPK (pERK1/2), PI3K (pAKT), and induces proliferation (Ki-67) in human PBMCs, with kinetics and efficacy similar to IL-2. Agonism is attributable to direct activation of IL-2/15Rβγc as shown by dependence on Rβ expression in test cells, and insensitivity to blockade by neutralizing antibodies against IL-2 and IL-15. At concentrations greatly exceeding that required for maximum IL-2/15R activation in vitro, MDK-202 does not interfere with the activities of other Rγc family receptors. The predicted immunogenicity potential for MDK-202 is very low, and in the unlikely event of MDK-202-induced ADA, neutralization of endogenous IL-2 or IL-15 would not be expected. MDK-202 is highly stable in human serum, showing no significant degradation after 4 days at 37C. In ex vivo human PBMC and in vivo studies in normal mice, hPBMC-engrafted NCG mice, and non-human primates, MDK-202 exhibited extended half-life, and activation, proliferation, and population dynamics of lymphocytes similar to those induced by ‘non-Rα’ variants of IL-2.ConclusionsMDK-202 is an attractive alternative to IL-2/15 variants for use in immuno-oncology therapy. Constructed without reference or similarity to cytokine or receptor structures or contacts, the peptidyl agonist component (MDK1169) is completely unique, and shown to be active when fused to other proteins such as anti-PD-1 antibodies and other cytokine receptor agonists.Ethics ApprovalAnimal studies were performed by Charles Rivers Laboratories, as approved by the CRL Instuition Ethics Board with the following study and approval numbers:CRL-220007; 20222440 : PK Cynomolgus Monkeys: BA-e451;BA-e451: PD NCG mice BA-e411; BA-e411:PD NCG miceKey 2152; US19001: PK mice: The use of human PBMC in this study was authorized under Minimal Risk Research Related Activities at Stanford Blood Center (SQL 79075)

scholarly journals Systemic Delivery of Oncolytic Adenovirus to Tumors Using Tumor-Infiltrating Lymphocytes as Carriers

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 978
Author(s):  
Joao Santos ◽  
Camilla Heiniö ◽  
Dafne Quixabeira ◽  
Sadia Zafar ◽  
James Clubb ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Human Lymphocytes ◽  
Tumor Infiltrating Lymphocytes ◽  
Complete Response ◽  
Oncolytic Adenovirus ◽  
Systemic Delivery ◽  
Systemic Injection ◽  
Infiltrating Lymphocytes

Immunotherapy with tumor-infiltrating lymphocytes (TIL) or oncolytic adenoviruses, have shown promising results in cancer treatment, when used as separate therapies. When used in combination, the antitumor effect is synergistically potentiated due oncolytic adenovirus infection and its immune stimulating effects on T cells. Indeed, studies in hamsters have shown a 100% complete response rate when animals were treated with oncolytic adenovirus coding for TNFa and IL-2 (Ad5/3-E2F-D24-hTNFa-IRES-hIL2; TILT-123) and TIL therapy. In humans, one caveat with oncolytic virus therapy is that intratumoral injection has been traditionally preferred over systemic administration, for achieving sufficient virus concentrations in tumors, especially when neutralizing antibodies emerge. We have previously shown that 5/3 chimeric oncolytic adenovirus can bind to human lymphocytes for avoidance of neutralization. In this study, we hypothesized that incubation of oncolytic adenovirus (TILT-123) with TILs prior to systemic injection would allow delivery of virus to tumors. This approach would deliver both components in one self-amplifying product. TILs would help deliver TILT-123, whose replication will recruit more TILs and increase their cytotoxicity. In vitro, TILT-123 was seen binding efficiently to lymphocytes, supporting the idea of dual administration. We show in vivo in different models that virus could be delivered to tumors with TILs as carriers.

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