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Compositions and methods for delivery of immune cells to treat un-resectable or non-resected tumor cells and tumor relapse

a technology of immune cells and tumors, applied in the field of immune cells for treating unresectable or non-resected tumor cells and tumor relapse, can solve the problems of cancer relapse after surgery, cancer relapse remains cancer relapse is often a major clinical problem, so as to achieve the effect of effective treatment options

Inactive Publication Date: 2016-01-14
FRED HUTCHINSON CANCER RES CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a composition for treating tumors that cannot be surgically resected or managed by palliative surgery. The composition includes a structure, lymphocytes, lymphocyte-adhesion moieties, and lymphocyte-activating moieties, which can be surgically implanted at the tumor site or resection bed. The composition can act as an active depot, releasing lymphocytes into the tumor area to purge residual tumor cells. At the same time, the composition can also activate the subject's immune system to destroy distant deposits of tumor cells, reducing the risk of metastatic relapse after resection. This invention provides a clinical device that can save patients from complicated surgeries, costly hospital stays, and expensive palliative care.

Problems solved by technology

Some cancers, such as advanced pancreatic cancers, are un-resectable at the time of their discovery.
Additionally, cancer relapse following surgery remains a major clinical problem and is frequently the ultimate cause of death.
Relapse often occurs because tumors cannot be completely resected, as they invade vital organs and / or lack distinct borders.
However, two major hurdles remain that seriously limit the use of ACT to prevent tumor relapse: infused lymphocytes inefficiently traffic to tumor, and even if a limited number of administered lymphocytes infiltrate tumor tissue, they poorly persist.
Accordingly, although some patients benefit enormously from ACT, in most cases the tumor will ultimately grow back, with lethal consequences.

Method used

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  • Compositions and methods for delivery of immune cells to treat un-resectable or non-resected tumor cells and tumor relapse
  • Compositions and methods for delivery of immune cells to treat un-resectable or non-resected tumor cells and tumor relapse
  • Compositions and methods for delivery of immune cells to treat un-resectable or non-resected tumor cells and tumor relapse

Examples

Experimental program
Comparison scheme
Effect test

example 1

Generation and Ex Vivo Expansion of 4T1 Breast Tumor-Reactive Mouse T-Cells

[0133]To model clinical ACT, in which tumor-reactive T-cells are isolated from patients and expanded in the laboratory, an established protocol to obtain breast tumor-specific T-cells from BALB / c mice (Restifo, Nat Rev Immunol 12, 269-281 (2012) which is incorporated by reference herein for its teachings regarding the same) was optimized. First, a 4T1 mammary carcinoma cell line that expresses the costimulatory ligands B7.1 and 4-1 BBL was generated using retroviral vectors (FIGS. 4A and 4B). This genetic modification helps the immune system recognize 4T1 tumor antigens as foreign. Irradiated 4T1 B7.1 / 4-1 BBL (hereafter 4T1-STIM) cells act as a whole cell cancer vaccine and prime tumor-specific T-cells in BALB / c mice following tail-base injection (4×106 tumor cells). To enhance further vaccine-driven immune responses, the adjuvants CpG oligodeoxynucleotide and poly(I:C) were mixed with 4T1-STIM cells before i...

example 2

Tumor-Reactive T-Cells Injected Intravenously or Locally into the Tumor Resection Bed Fail to Prevent Tumor Relapse Due to Inefficient Tumor Homing and / or Poor Persistence

[0134]Whether standard intravenous injections of 4T1 tumor-reactive T-cells could reduce cancer relapse emanating from incompletely excised 4T1 tumor was assessed. The chosen 4T1 breast tumor model very closely mimics the tumor growth and metastatic spread of human breast cancer to lymph nodes, liver, lung, and bone. Tumor cells, retrovirally tagged with Gaussia luciferase for bioluminescence imaging, are easily transplanted into the right mammary gland of BALB / c mice and develop tumors that are ˜10 mm in size after two weeks. At that time point, mice were preconditioned for the adoptive transfer of T-cells by removing homeostatic cytokine sinks by lymphodepletion (250 mg / kg cyclophosphamide, injected intraperitoneally). The following day, tumors were resected, leaving behind 0.1-1% residual disease as quantified b...

example 3

Porous Polysaccharide Scaffolds Coated with Collagen-Mimetic Peptide Support Rapid “Lymph Nodelike” Motility and Sustain the Viability of Embedded T-Cells

[0137]To address the issues noted above, implantable compositions were created to produce a new microenvironment at the tumor resection site conducive to the sustained proliferation of transferred lymphocytes. The compositions can be used to deliver tumor-reactive lymphocytes to residual tumor following resection while sustaining their effector function and survival. To function as a lymphocyte delivery and release platform, a composition needs to provide sufficient mechanical support for embedded cells, a cell-adhesive coating to enable loaded cells to migrate through the material and exit into tissue, and appropriate stimulatory signals to trigger cell proliferation.

[0138]As an example, under physiological conditions, T-cells migrate in peripheral tissue along collagen fibers. Whether anchoring the collagen-mimetic peptide GFOGER...

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Abstract

The present disclosure provides compositions and methods for the delivery of immune cells to treat un-resectable or non-resected tumor cells and tumor relapse. The compositions comprise (i) a structure comprising an injectable polymer or scaffold comprising pores; (ii) lymphocytes disposed within the structure, (iii) at least one lymphocyte-adhesion moiety associated with the structure; and (iv) at least one lymphocyte-activating moiety associated with the structure, and optionally an immune stimulant.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to and the benefit of U.S. Provisional Patent Application No. 61 / 752,423 filed Jan. 14, 2013, and 61 / 900,922 filed Nov. 6, 2013, the entire contents of both of which application are incorporated by reference herein.FIELD OF THE DISCLOSURE[0002]The present disclosure provides compositions and methods for the delivery of immune cells to treat un-resectable or non-resected tumor cells and tumor relapse. The compositions comprise (i) a structure; (ii) lymphocytes, (iii) lymphocyte-adhesion moieties; and (iv) lymphocyte-activating moieties, and optionally an immune stimulant.BACKGROUND OF THE DISCLOSURE[0003]Some cancers, such as advanced pancreatic cancers, are un-resectable at the time of their discovery. Additionally, cancer relapse following surgery remains a major clinical problem and is frequently the ultimate cause of death. Relapse often occurs because tumors cannot be completely resected, as they invad...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K35/17A61K9/00A61K9/14A61K39/44A61K45/06C07K16/28
CPCA61K35/17A61K9/146A61K39/44C07K16/2878A61K9/0024A61K45/06C07K16/2818C07K16/2809A01K67/0271C12N5/0694A01K2267/0331C12N2510/00C12N2533/54C12N2533/74A01K2207/12A01K2227/105A61K2239/38A61K39/4611A61K2239/31A61K2239/49A61K39/4644
Inventor STEPHAN, MATTHIAS
Owner FRED HUTCHINSON CANCER RES CENT
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