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Methods of growing tumor infiltrating lymphocytes in gas-permeable containers

a technology of infiltrating lymphocytes and gas-permeable containers, which is applied in the direction of cell culture active agents, drug compositions, antibody medical ingredients, etc., can solve the problems of technical, regulatory, logistical and logistic challenges that are introduced

Inactive Publication Date: 2017-06-01
UNITED STATES OF AMERICA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent is about a method for promoting the regression of cancer in mammals by obtaining tumor tissue samples, culturing them to expand the number of tumor infiltrating lymphocytes (TIL), and then administering the expanded TIL to the mammal. The method also involves using irradiated allogeneic or autologous feoder cells to expand the TIL. The technical effect of the patent is to provide a more effective way to treat cancer by utilizing TIL therapy.

Problems solved by technology

These procedures have introduced technical, regulatory, and logistic challenges to the successful use of TIL as a biological therapy.

Method used

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  • Methods of growing tumor infiltrating lymphocytes in gas-permeable containers

Examples

Experimental program
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Effect test

example 1

[0059]This example demonstrates that TIL cultured in gas-permeable containers is better than, or at least comparable to, that in a 24-well plate.

[0060]The growth of TIL from tumors using gas permeable flasks with a 40 mL capacity and 10 cm2 gas permeable silicone bottom (G-Rex10, Wilson Wolf Manufacturing Corporation, New Brighton, Minn., USA (providing about 10 cm2 of surface area for growth of the TIL)) or 24-well plates (Corning Corning, N.Y.) was compared. A total of 14 melanoma samples were tested, including 9 freshly prepared tumor digests (Table 1A) and 5 thawed samples from previously frozen tumor digests (Table 1B). TIL from frozen tumor from patient 2653 were not able to be cultured in either the G-Rex10 or 24-well plates. Except for one fresh sample (#3522), the ratio of harvested TIL to initially seeded cells at day 17 to 29 was similar to or better in the G-Rex10 flasks than in the 24-well plate (Table 1A and 1B).

TABLE 1AComparison of initial TIL culture in G-Rex10flask...

example 2

[0063]This example demonstrates that the culture of TIL from tumor fragments in gas permeable flasks produces a greater number of TIL as compared to culture in 24-well plates after 7 to 13 days.

[0064]The growth of TIL from tumor fragments in G-Rex10 flasks or 24-well plates was next compared. For each tumor sample, fragments approximately 1 to 8 mm3 in size were seeded into 24-well plates at 1 piece per well and into G-Rex10 flasks at 5, 10, 20, or 30 pieces per flask. The growth of TIL from 2 lymph nodes and 1 liver metastasis was assessed (Table 2). TIL could be grown from tumor fragments in both gas-permeable flasks and 24-well plates, but after 7 to 13 days greater quantities of TIL were obtained from the G-Rex10 flasks than the wells (Table 2).

TABLE 2Initial TIL culture using tumor fragments in G-Rex10 flasks and 24-well plates.Number of cellsPatient# of TIL PhenotypeNumber TILTIL(% TIL expressing each antigen)and TumorCultureTumor TIL#perViabilityCD3+CD3+SourceVesselFragments*...

example 3

[0066]This example demonstrates the kinetics of TIL growth in gas-permeable flasks.

[0067]In order to assess the kinetics of TIL growth in gas-permeable cultureware, TIL from one patient were cultured in G-Rex100 flasks seeded at a density of 5×106 and 10×106 cells per flask. The cells were counted daily after day 6. On Day 6 the number of cells in the G-Rex100 flask seeded at 5×106 cells was 255×106 cells and at 10×106 cells was 300×106 cells. The quantity of TIL in G-Rex100 flasks seeded at each cell density increased steadily until day 9, but there was little increase in cell counts between days 9 and 10. After 10 days 906×106 cells were harvested from flasks seeded with 5×106 TIL and 1,050×106 cells from flasks seeded with 10×106 TIL. Although TIL expanded well for 9 days, in order to keep the G-Rex100 flask expansion process similar to REP in T-flasks and gas-permeable bags where TIL are transferred from T-flasks to bags on day 7, further studies focused on TIL expansion in the ...

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Abstract

An embodiment of the invention provides a method of promoting regression of cancer in a mammal comprising obtaining a tumor tissue sample from the mammal; culturing the tumor tissue sample in a first gas permeable container containing cell medium therein; obtaining tumor infiltrating lymphocytes (TIL) from the tumor tissue sample; expanding the number of TIL in a second gas permeable container containing cell medium therein using irradiated allogeneic feeder cells and / or irradiated autologous feeder cells; and administering the expanded number of TIL to the mammal. Methods of obtaining an expanded number of TIL from a mammal for adoptive cell immunotherapy are also provided.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This patent application claims the benefit of U.S. Provisional Patent Application No. 61 / 466,200, filed Mar. 22, 2011, which is incorporated by reference in its entirety herein.BACKGROUND OF THE INVENTION[0002]Adoptive cell therapy (ACT) using tumor infiltrating lymphocytes (TIL) can lead to positive, objective, and durable responses in cancer patients. However, this therapy can involve sophisticated cell processing techniques and equipment. These procedures have introduced technical, regulatory, and logistic challenges to the successful use of TIL as a biological therapy. Accordingly, there is a need in the art for improved methods for growing TIL for use in adoptive cell therapy.BRIEF SUMMARY OF THE INVENTION[0003]An embodiment of the invention provides a method of promoting regression of cancer in a mammal comprising obtaining a tumor tissue sample from the mammal; culturing the tumor tissue sample in a first gas permeable container con...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N5/078A61K39/00A61K35/12
CPCC12N5/0634A61K39/0011C12N2501/2302A61K2039/5158C12N2501/2315C12N2502/11C12N2501/515A61K2035/124C12N5/0638A61P35/00A61K39/4611A61K2239/57A61K39/4644
Inventor ROSENBERG, STEVEN A.DUDLEY, MARK E.STRONCEK, DAVIDSABATINO, MARIANNAJIN, JIANJIANSOMERVILLE, ROBERTWILSON, JOHN R.
Owner UNITED STATES OF AMERICA
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