Constitutive expression of costimulatory ligands on adoptively transferred T lymphocytes

a technology of costimulatory ligands and t lymphocytes, which is applied in the field of imitation expression of costimulatory ligands on adoptively transferred t lymphocytes, can solve the problems of no curative treatment for hormone refractory, efficient t cell priming and tumor rejection, and achieve the effects of preventing the occurrence or recurrence of disease, reducing any direct or indirect pathological consequences, and preventing metastases

Active Publication Date: 2012-08-28
MEMORIAL SLOAN KETTERING CANCER CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]In yet another aspect, the invention provides a method of modulating an immune response in a subject, the method comprising administering an effective amount of an immunoresponsive cell of any previous aspect. In one embodiment, the method increases or reduces an immune response. In another embodiment, the method increases self-tolerance or increases tolerance to an organ transplant.
[0011]In another aspect, the invention provides a method of enforcing tolerance in a subject, the method comprising administering an effective amount of an immunoresponsive cell comprising a receptor that binds an antigen and a vector encoding a co-stimulatory ligand. In one embodiment, the method prevents or reduces an autoimmune disease or a disease associated with allogeneic transplantation.
[0050]By “enforcing tolerance” is meant preventing the activity of self-reactive cells or immunoresponsive cells that target transplanted organs or tissues.
[0068]As used herein, “treatment” refers to clinical intervention in an attempt to alter the disease course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Therapeutic effects of treatment include, without limitation, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastases, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. By preventing progression of a disease or disorder, a treatment can prevent deterioration due to a disorder in an affected or diagnosed subject or a subject suspected of having the disorder, but also a treatment may prevent the onset of the disorder or a symptom of the disorder in a subject at risk for the disorder or suspected of having the disorder.

Problems solved by technology

At present, there is no curative treatment for hormone refractory, metastatic prostate cancer.
Among the mechanisms limiting efficient T cell priming and tumor rejection is the inherent absence of costimulatory ligands on many malignancies.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

T Cells Co-expressing CD80 and 4-1BBL Elicit Robust Proliferative Responses after Cyclic Stimulations through their Endogenous T Cell Receptor or through a Chimeric Antigen Receptor without Antigen Presenting Cell (APC)-provided Costimulation

[0140]To assess whether constitutive expression of costimulatory ligands in T cells could substitute for APC-mediated costimulation, the T cell responses of human primary T cells were first investigated in three experimental systems. Using anti-CD3 (OKT3)-mediated T cell activation, the expansion of peripheral blood T lymphocytes transduced with CD80 and 4-1BBL was quantified (FIG. 1a), which were compared to T cells transduced with either ligand alone or none. Recurrent T cell receptor (TCR)-stimulation alone in the absence of costimulatory ligands failed to expand T cells and rapidly induced a decline in T cell number following the first restimulation (FIG. 1b). In sharp contrast, OKT3-stimulated CD80+4-1BBL+ T cells triggered a mean 237-fold ...

example 2

T Cells Co-expressing CD80 and 4-1BBL Eradicate Established, Systemic Tumors

[0143]To investigate the potency of our CD80+4-1BBL+ T cells in vivo, a model of multifocal, established prostate cancer utilizing PSMA−PC-3 tumor cells (Gong et al., Neoplasia 1:123-7, 1999, which is hereby incorporated by reference in its entirety) was developed. Using dual-modality bioluminescence and magnetic resonance imaging, tumors were visualized four weeks after intravenous inoculation, prior to initiating adoptive T cell therapy. The lungs, cervical lymph nodes, bone marrow, and liver were identified as the main sites of disease (FIG. 2a). In this model, animals were treated four weeks after tumor inoculation with a single intravenous infusion of 8×106 PSMA-targeted T cells, expressing either CD80, 4-1BBL, both, or neither.

[0144]In control mice treated with 8×106 CD19-targeted T cells, which, like untransduced T cells, fail to lyse PSMA+ tumor targets in vitro tumor burden steadily progressed until...

example 3

In Vivo T Cell Expansion is Robust and Antigen-Specific

[0145]To track and quantify in vivo T-cell migration and accumulation in relation to tumor localization and tumor burden, adoptively transferred T cells were additionally marked with Click Beetle Red-luciferase (Ponomarev et al., Eur J Nucl Med Mol Imaging. 2004 May; 31(5):740-51) (CBR-luc, FIG. 3a). Serial imaging of mice treated with Pz1+ T cells showed a progressive increase in signal that reached a peak four days after T cell injection (FIG. 3b). A low-level signal remained detectable up to day 18. In the case of Pz1+CD80+4-1BBL+ T cells, peak signal was detected on day 8 (41-fold higher nadir photon count than Pz1+ T cells, p=0.0009), which was followed by a gradual signal decline, although bioluminescence could still be detected until day 100 in some animals (FIG. 3b). Importantly, the effect of CD80 and 4-1BBL co-expression was abrogated in 19z1+ T lymphocytes (FIG. 3b), consistent with the need for antigen stimulation fo...

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Abstract

The present invention provides immunoresponsive cells, including T cells, cytotoxic T cells, regulatory T cells, and Natural Killer (NK) cells, expressing at least one of an antigen-recognizing receptor and a co-stimulatory ligand and methods of use therefore for the treatment of neoplasia and other pathologies where an increase in an antigen-specific immune response is desired.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application is the U.S. national phase, pursuant to 35 U.S.C. §371, of PCT international application Ser. No. PCT / US2008 / 004251, filed Mar. 31, 2008, designating the United States and published in English on Oct. 9, 2008 as publication WO 2008 / 121420 A1, which claims priority to U.S. provisional application Ser. No. 60 / 921,144, filed on Mar. 30, 2007. The entire contents of the aforementioned patent applications are incorporated herein by this reference.[0002]Each of the applications and patents cited in this text, as well as each document or reference cited in each of the applications and patents (including during the prosecution of each issued patent; “application cited documents”), and each of the PCT and foreign applications or patents corresponding to and / or claiming priority from any of these applications and patents, and each of the documents cited or referenced in each of the application cited documents, are hereby expressly i...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C12N5/16
Inventor SADELAIN, MICHELSTEPHAN, MATTHIAS
Owner MEMORIAL SLOAN KETTERING CANCER CENT
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