Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-12-20
2003-07-15
Caputa, Anthony C. (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C424S197110, C424S198100, C514S800000, C530S385000
Reexamination Certificate
active
06593096
ABSTRACT:
DETAILED DESCRIPTION OF THE INVENTION
1. Field of the Invention
The present invention relates to an agent for cancer immunotherapy containing bacterial components as an active ingredient, and more particularly, a new agent used independently for cancer patients having immuno-competence. More specifically, the invention relates to a new immunotherapeutic agent capable of preventing recurrence of cancer or generation of secondary cancer including post-operative metastasis, in patients having immuno-competence which can be determined by an ability of inducing interferon-&ggr; (IFN-&ggr;) and the like. The invention further relates to a new method for determining immuno-competence of a patient by measuring an ability of inducing IFN-&ggr; and so on, which is used for the present cancer immunotherapy.
2. Prior Art
An agent for cancer immunotherapy containing bacterial components as an active ingredient is known, and particularly, numerous clinical data obtained by the cancer immunotherapy using BCG (Bacille Calmette-Guerin) have been accumulated.
There have been widely reported the results of clinical trials on cancer immunotherapy, in particular, since clinical effects of BCG-immunotherapeutic agents were confirmed by Mathe et al. in acute lymphocytic leukemia and by Molton et al. in melanoma in the latter half of 1960's. However, since the clinical data have been stochastically analyzed for the survival rates in the randomized controlled trial, ineffective cases have increased in immunotherapy with BCG, resulting in the doubt of its effectiveness. After that, BCG was used only supplementarily in chemotherapy. In addition to BCG, bacteria such as
C. parvum
, hemolytic Streptococcus, and OK432 have also been used. However, in cancer immunotherapy with those bacteria, some were effective and some were ineffective like BCG, and their effectiveness has not been established yet.
Recently, in BCG-immunotherapy, cell wall skeleton (CWS) prepared from cell walls, obtained by grinding bacterial cells and then fractionating by centrifugation, has been used to make improvements in terms of prevention of side effects and regulation of dose and frequency of administration. Clinical trials for lung cancer, leukemia, stomach cancer and the like using BCG-CWS or N. rubra-CWS were conducted under randomized design by Yamamura et al. of Osaka University and their associates. Though the results showed the stochastically significant prolongation of survival time, it was incomplete as a cancer immunotherapy. At present, an established reputation for such immunotherapeutic agents can be seen in Iwanamikoza, Immunoscience 7, Transplantation Immunity and Tumor Immunity, Feb. 29, 1984, p.302, which reads “The results, as already stated have failed to show constant effectiveness as an immunotherapeutic agent, because we obtained adverse, ineffective, or insignificant effect. The major reason, among others, for such inconsistency is attributed to the fact that the statistical significance test was performed between the group in which immunotherapy was used as a supplemental therapy and the group in which immunotherapy was not used as a supplemental therapy. Thus, these results suggest the limit of the immunotherapy which does not exert direct anti-cancer effects.”
The inventors had doubts about the ways in which the cancer immunotherapy using BCG-CWS has been done in the past, analyzed the problems contained in this immunotherapy, and noticed the fact that such immunotherapy had been conducted together with a therapy which has a strong immuno-suppressive effect, such as anti-cancer drug and radiation. The inventors thought that a combination of immunostimulation therapy using BCG-CWS, N.rubra-CWS and so on, and a chemotherapy having immuno-suppressive effect would offset the characteristics of each therapies, and therefore, the combination contains discrepancy. Then, the inventors considered that, in order to show the effectiveness of the cancer immunotherapy with BCG-CWS, N.rubra-CWS or the like, an establishment of administration method which can easily induce immunostimulation, and selection of patients having suitable immuno-competence would be important.
The inventors have discovered that a therapy with independent use of BCG-CWS alone after the initial treatment has shown excellent therapeutic effects not found in the combination of the therapy with BCG-CWS and chemotherapy (Pro. Japan Acad.,70,Ser.B 205-209(1994)). It was also found that, based on the analysis of peripheral blood from treated patients, patients who showed evident induction of IFN-&ggr; by intradermal administration of BCG-CWS survived in good health, including complete cure, and on the other hand, patients who did not show the induction of IFN-&ggr; died in a short time. The inventors have additionally found that the induction of IFN-&ggr; by inoculation of BCG-CWS directly correlates to anticancer effects (Japanese Cancer Association, 54th Meeting, No.2411, 1995).
According to the above findings, the inventors made extended study in order to establish a cancer immunotherapy using bacterial components alone as an active ingredient. As a result, it was found that CD28 as well as IFN-&ggr; and G-CSF are useful as a marker of immuno-competence after inoculation of bacterial components in order to recognize a patient who has immuno-competence suitable for the present therapy. The inventors also discovered that an initial therapy has a great influence on the maintenance of an appropriate immuno-competence of a patient, and selection of such initial therapy is of great importance.
The present invention is based on the above findings.
The cancer immunotherapy which has been established by the present invention is summarized as follows.
The immunotherapy with BCG-CWS and the like is effective, as a matter of course, only in patients who have immuno-competence. Since the immuno-competence is affected by initial therapy to be used, it is essential that the therapy with independent use of BCG-CWS alone should be performed after removing as much cancer cells as possible by, for example, surgical operation, and discontinuing a chemotherapy or radiation which possibly decreases immuno-competence of patients.
Upon inoculation of BCG-CWS, a series of transient alterations are observed in components of peripheral blood from a patient. The alterations closely relate to the effectiveness of the immunotherapy as follows:
(1) Alterations in components of peripheral blood from a patient to whom the immunotherapy was effective.
As for cellular components, increase in leukocytes, particularly increase in granulocytes, and decrease in lymphocytes (continue about 24 hours) are found, with the increase and decrease having their peaks at from about 15 hours to about 18 hours after inoculation.
As for cytokines, increase in IFN-&ggr; (continues about 30 hours) and G-CSF (continues about 1 week) is found.
As for markers on the surface of T cell, increase in high CD28-positive lymphocytes (continues about 4-6 weeks) is found.
(2) Alterations in components of peripheral blood from patients to whom immunotherapy was not effective.
No alteration of cellular components, cytokines, or markers on the surface of T-cell was found.
In three patients to whom immunothrapy was effective, increase of CD28-positive lymphocytes was not found. At the beginning of the therapy, those patients continued to show recovery. However, metastasis to the brain was found around after 2 years in two patients and they eventually died.
Accordingly, we considered that IFN-&ggr; and CD28 are useful as markers to know immuno-competence which gives anticipation on the results of the therapy. Influence of pre-treatment including initial therapy on the immuno-competence was investigated, especially in terms of inducibility of IFN-&ggr;, to give the following findings.
(1) In about 90% of the patients who did not receive any pre-treatment, such as chemotherapy and radiation therapy, which may influence to immuno-competence, induction of IFN-&ggr; was observed owing to a therapy with independen
Azuma Ichiro
Hayashi Akira
Toyoshima Kumao
Birch & Stewart Kolasch & Birch, LLP
Caputa Anthony C.
Davis Natalie
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