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Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy.

ABSTRACT: Despite the recent successes of using immune modulatory Abs in patients with cancer, autoimmune pathologies resulting from the activation of self-reactive T cells preclude the dose escalations necessary to fully exploit their therapeutic potential. To reduce the observed and expected toxicities associated with immune modulation, here we describe a clinically feasible and broadly applicable approach to limit immune costimulation to the disseminated tumor lesions of the patient, whereby an agonistic 4-1BB oligonucleotide aptamer is targeted to the tumor stroma by conjugation to an aptamer that binds to a broadly expressed stromal product, VEGF. This approach was predicated on the premise that by targeting the costimulatory ligands to products secreted into the tumor stroma, the T cells will be costimulated before their engagement of the MHC-peptide complex on the tumor cell, thereby obviating the need to target the costimulatory ligands to noninternalizing cell surface products expressed on the tumor cells. Underscoring the potency of stroma-targeted costimulation and the broad spectrum of tumors secreting VEGF, in preclinical murine tumor models, systemic administration of the VEGF-targeted 4-1BB aptamer conjugates engendered potent antitumor immunity against multiple unrelated tumors in subcutaneous, postsurgical lung metastasis, methylcholantrene-induced fibrosarcoma, and oncogene-induced autochthonous glioma models, and exhibited a superior therapeutic index compared with nontargeted administration of an agonistic 4-1BB Ab or 4-1BB aptamer.

SUBMITTER: Schrand B

PROVIDER: S-EPMC5502823 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy.

Schrand Brett B Berezhnoy Alexey A Brenneman Randall R Williams Anthony A Levay Agata A Kong Ling-Yuan LY Rao Ganesh G Zhou Shouhao S Heimberger Amy B AB Gilboa Eli E

Cancer immunology research 20140617 9

Despite the recent successes of using immune modulatory Abs in patients with cancer, autoimmune pathologies resulting from the activation of self-reactive T cells preclude the dose escalations necessary to fully exploit their therapeutic potential. To reduce the observed and expected toxicities associated with immune modulation, here we describe a clinically feasible and broadly applicable approach to limit immune costimulation to the disseminated tumor lesions of the patient, whereby an agonist ...[more]

PMID: 24938283

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Project description:BackgroundImmune checkpoint inhibitors have revolutionized cancer therapy, but many patients fail to respond or develop resistance, often due to reduced T cell activity. Costimulation via 4-1BB has emerged as a promising approach to enhance the effector function of antigen-primed T cells. Bispecific T cell-engaging (TCE) antibodies are an effective way to provide tumor-specific T cell receptor-mediated signaling to tumor-infiltrating lymphocytes. mRNA-based delivery of bispecific antibodies, offer a novel approach to enhance tumor-specific immune responses while minimizing adverse effects.MethodsTwo bispecific antibodies were generated: the EGFR x CD3 TCE antibody (LiTE) and the PD-L1 x 4-1BB costimulatory antibody (LiTCo), which was further fused to a high FcRn albumin variant (Albu-LiTCo). The mRNA encoding these bispecific antibodies contains an N1-methylpseudouridine modified nucleoside and regulatory sequences to ensure proper expression and stability. A series of in vitro assays and cell-based analyses were performed to characterize both antibodies. The in vivo efficacy of the mRNA-encoded bispecific antibodies was evaluated in xenograft tumor models expressing EGFR.ResultsWe investigated the combined effect of two mRNA-encoded Fc-free bispecific antibodies with complementary mechanisms of action: an EGFR-targeting TCE and a half-life extended PD-L1 x 4-1BB costimulatory antibody. The mRNAs encoding both bispecific LiTERNA and Albu-LiTCoRNA, showed similar binding specificity and in vitro function to their protein analogues. Pharmacokinetic studies demonstrated sustained expression of both bispecific antibodies following intravenous administration of the mRNAs formulated using a polymer/lipid-based nanoparticle (LNP) but different pharmacokinetic profiles, shorter for the TCE and longer for the PD-L1 x 4-1BB. When administered as a mRNA-LNP combination (ComboRNA), the growth of EGFR-positive tumors in immunocompetent mice was significantly inhibited, resulting in tumor regression in 20% of cases with no associated toxicity. Histological analysis confirmed increased T cell infiltration in the tumors treated with LITERNA and ComboRNA. Repeated administration resulted in sustained production of bispecific antibodies with different exposure cycles and potent antitumor activity with a favorable safety profile.ConclusionsThese results highlight the potential of combining two mRNA-encoded bispecific antibodies with different mechanisms of action and programmable half-life for cancer immunotherapy.

Project description:Chimeric antigen receptor (CAR) T cell immunotherapy is emerging as a powerful strategy for cancer therapy; however, an important safety consideration is the potential for off-tumor recognition of normal tissue. This is particularly important as ligand-based CARs are optimized for clinical translation. Our group has developed and clinically translated an IL13(E12Y) ligand-based CAR targeting the cancer antigen IL13Rα2 for treatment of glioblastoma (GBM). There remains limited understanding of how IL13-ligand CAR design impacts the activity and selectivity for the intended tumor-associated target IL13Rα2 versus the more ubiquitous unintended target IL13Rα1. In this study, we functionally compared IL13(E12Y)-CARs incorporating different intracellular signaling domains, including first-generation CD3ζ-containing CARs (IL13ζ), second-generation 4-1BB (CD137)-containing or CD28-containing CARs (IL13-BBζ or IL13-28ζ), and third-generation CARs containing both 4-1BB and CD28 (IL13-28BBζ). In vitro coculture assays at high tumor burden establish that second-generation IL13-BBζ or IL13-28ζ outperform first-generation IL13ζ and third-generation IL13-28BBζ CAR designs, with IL13-BBζ providing superior CAR proliferation and in vivo antitumor potency in human xenograft mouse models. IL13-28ζ displayed a lower threshold for antigen recognition, resulting in higher off-target IL13Rα1 reactivity both in vitro and in vivo. Syngeneic mouse models of GBM also demonstrate safety and antitumor potency of murine IL13-BBζ CAR T cells delivered systemically after lymphodepletion. These findings support the use of IL13-BBζ CARs for greater selective recognition of IL13Rα2 over IL13Rα1, higher proliferative potential, and superior antitumor responsiveness. This study exemplifies the potential of modulating factors outside the antigen targeting domain of a CAR to improve selective tumor recognition.SignificanceThis study reveals how modulating CAR design outside the antigen targeting domain improves selective tumor recognition. Specifically, this work shows improved specificity, persistence, and efficacy of 4-1BB-based IL13-ligand CARs. Human clinical trials evaluating IL13-41BB-CAR T cells are ongoing, supporting the clinical significance of these findings.

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Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy.

Publications

Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy.

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