Modulation of the sensitivity of tumor cells to chemotherapeutics

• US 6,093,381 A
• Filed: 12/10/1997
• Issued: 07/25/2000
• Est. Priority Date: 07/13/1994
• Status: Expired due to Fees

• Current Assignee: The Ohio State University Research Foundation
• Original Assignee: Neoprobe Corporation
• Inventors: Triozzi, Pierre L., Kim, Julian A.
• Primary Examiner(s): MINNIFIELD, NITA M
• Application Number:
  US08/988,341
• Time in Patent Office: 958 Days
• Field of Search: 424/1.49, 424/9.1, 424/9.322, 424/1.41, 424/1.17, 424/93.7, 424/85.1, 424/85.2, 424/93.1, 424/155.1, 424/152.1, 424/520, 424/534, 435/372.2
• US Class Current: 424/1.49
• CPC Class Codes: A61K 2039/5158 Antigen-pulsed cells, e.g. T-cells
• CPC Class Codes: A61K 2121/00 Preparations for use in therapy
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/461 characterised by the cell type used
• CPC Class Codes: A61K 39/4644 Cancer antigens
• CPC Class Codes: A61K 51/10 Antibodies or immunoglobulins; Fragments thereof , the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
• CPC Class Codes: C12N 2501/23 Interleukins [IL]
• CPC Class Codes: C12N 2501/24 Interferons [IFN]
• CPC Class Codes: C12N 2501/515 CD3, T-cell receptor complex
• CPC Class Codes: C12N 5/0636 T lymphocytes

Abstract

Disclosed is a method for improving the treatment of a cancer patient which is undergoing (adjuvant) chemotherapy. Prior to or concomitant with the patient receiving adjuvant chemotherapy, the patient is administered mitogenically stimulated lymph node lymphocytes or the supernatant therefrom. The lymph node lymphocytes are patient excised lymph node lymphocytes enriched in tumor reactive cells, such as CD4+ tumor reactive cells. Radiolabeled locators (e.g., antibodies) can be used along with a portable radiation detector to intraoperatively determine which lymph nodes bear lymph node lymphocytes enriched in tumor reactive cells. The patient excised lymph node lymphocytes enriched in tumor reactive cells then are subjected to mitogenic stimulation for their expansion and administration to the patient.

Claims

1. A method for improving the activity of cancer chemotherapeutic agents which comprises:

(a) combining said chemotherapeutic agent with one or more of

(i) lymph node lymphocytes which have been cultured under mitogenic stimulation conditions, or

(ii) supernatant of said mitogenically stimulated cultured lymph node lymphocytes,

wherein said lymph node lymphocytes that are cultured under said mitogenic stimulation conditions are cancer patient excised lymph node lymphocytes enriched in tumor reactive cells, and

(b) administering such combination to said cancer patient.

2. The method of claim 1, wherein said excised lymph node lymphocytes are cultured in the presence of Interleukin-2 and anti-CD3 monoclonal antibody.

3. The method of claim 2, wherein said culturing further includes a tumor-associated glycoprotein (TAG) antigen.

4. The method of claim 2, wherein said culturing further includes neoplastic tissue comprising one or more of autologous neoplastic tissue or allogeneic neoplastic tissue.

5. The method of claim 4, wherein said neoplastic tissue has been inactivated prior to said culturing.

6. The method of claim 5, wherein said inactivation comprises radiation.

7. The method of claim 2, wherein the amount of Interleukin-2 ranges from between about 10 and 500 U/ml and the proportion of anti-CD3 monoclonal antibody ranges from between about 10 and 500 ng/ml.

8. The method of claim 4, wherein said culturing includes the use of serum-free media.

9. The method of claim 1, wherein said chemotherapeutic agents are administered after, or both before and after, said supernatant or said cultured lymph node lymphocytes are administered to said cancer patient.

10. The method of claim 1, wherein said cancer patient excised lymph node lymphocytes enriched in tumor reactive cells are cultured more than once under mitogenic stimulation conditions.

11. A method for improving the treatment of a cancer patient which is undergoing chemotherapeutic treatment with a chemotherapeutic agent, which comprises:

co-administering said chemotherapeutic agent to said patient along with one or more of;

(i) lymph node lymphocytes which have been cultured under mitogenic stimulation conditions, or

(ii) supernatant of said mitogenically stimulated cultured lymph node lymphocytes,

wherein said lymph node lymphocytes that are cultured under said mitogenic stimulation conditions are cancer patient excised lymph node lymphocytes enriched in tumor reactive cells.

12. The method of claim 11, wherein said excised lymph node lymphocytes are cultured in the presence of Interleukin-2 and anti-CD3 monoclonal antibody.

13. The method of claim 12, wherein said culturing further includes a tumor-associated glycoprotein (TAG) antigen.

14. The method of claim 12, wherein said culturing further includes neoplastic tissue comprising one or more of autologous neoplastic tissue or allogeneic neoplastic tissue.

15. The method of claim 14, wherein said neoplastic tissue has been inactivated prior to said culturing.

16. The method of claim 15, wherein said inactivation comprises radiation.

17. The method of claim 12, wherein the amount of Interleukin-2 ranges from between about 10 and 500 U/ml and the proportion of anti-CD3 monoclonal antibody ranges from between about 10 and 500 ng/ml.

18. The method of claim 14, wherein said culturing includes the use of serum-free media.

19. The method of claim 11, wherein co-administering includes administering said chemotherapeutic agents after, or both before and after, said supernatant or said cultured lymph node lymphocytes are administered.

20. The method of claim 11, wherein said cancer patient excised lymph node lymphocytes enriched in tumor reactive cells are cultured more than once under mitogenic stimulation conditions.