Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1997-11-10
2001-06-05
Wortman, Donna C. (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007240, C436S063000, C436S064000, C436S813000
Reexamination Certificate
active
06242202
ABSTRACT:
The present invention relates generally to a method of predicting the therapeutic response of a drug. More specifically, the invention relates to a method of predicting the therapeutic response of a drug directed towards a cancer in a human patient.
The response rate for immunomodulating drugs in the treatment of tumours is very low. The most efficient immunomodulating drugs, e.g. interferon or interleukin-2, in the treatment of the most responsive tumours (malignant melanoma and renal cell carcinoma) is only 15-20%. However, some patients achieve very valuable remissions. It would therefore be a considerable improvement if those patients who are most likely to respond to the of treatment could be identified. Several approaches have been used to try to develop such tests. Most of them are based on identification of immunosuppression or activation of certain cells of the immune system in patients with malignant tumours.
Immunosuppression in cancer patients have been demonstrated using various methods, e.g. reduced proliferative stimulation of PBL by mitogens (phytohemagglutinin, PHA and concanavalin A, ConA) or recall antigens (Candida, PPD etc.), reduced response to various antigens on vaccination. In some studies a correlation between the results of these tests and the prognosis of the patients have been reported (e.g. deGast et al., Cancer, 1975; Hilal et al., Am J Surg, 1977).
It has been repeatedly demonstrated that PBL from cancer patients have a significantly lower proliferative response (measured as incorporation of
3
H-TdR into newly synthesized DNA) to mitogens such as Phytohemagglutinin (PHA) and Concanavallin A (ConA) as compared to normal healthy controls (e.g. Catalona et al., J natl Cancer inst, 1980; Dean et al., Int J Cancer, 1977; Farinas et al., Cancer, 1991; Jerrels et al., Int J Cancer, 1978; Mantovani et al., Diagnostic and Clinical Immunology, 1987; Pehamberger and Knapp, J Invest Dermatol, 1981; Radhakrishna et al., Cancer, 1989; Richner et al., Cancer Immunol Immunother, 1991; Silverman et al., Surgery 1976; Tsubono et al., 1990). Generally, an immunosuppression identified by this technique increases with the advancement of the disease (Lui et al., Br J Cancer, 1975; Mantovani et al., Diagnostic and Clinical Immunology, 1987; Silverman et al., Surgery 1976). Thus, several reports on a correlation between inhibition of the proliferative response and the prognosis of the patients is not surprising. However, they have generally not been found to be useful in the clinical management of individual patients since this immunosuppression is stage dependent and large inter-individual variations are observed in these tests within the group of patients as well as within healthy controls (deGast et al., Cancer, 1975; Lui et al., Br J Cancer, 1975; Silverman et al., Surgery 1976).
Chretien et al. (Chretien et al.,Surgery, Gynecology and Obstetrics, 1973) found a reduced proliferative response to PHA before surgery in solid tumour patients compared to normal, age matched controls. In the group of cured patients at the three year follow up, the percentage of patients with a low level of lymphocyte reactivity was significantly lower compared with the group of patients with inoperable or recurrent disease. Similarly, in two other studies the response to PHA was found to correlate with the prognosis (Mekori et al., J Natl Cancer Inst, 1974; Watkins, Br J surg, 1976). In contrast, Hilal et al. (Hilal et al., Am J Surg, 1977) found no correlation between mitogen stimulation and recurrence of squamos cell carcinoma of the head and neck.
These tests have with a few exceptions not been used to predict therapeutic response to chemotherapy (Cheema and Hersh, Cancer, 1971; Jones et al., Clinical Oncology, 1980; Toge et al., Gann, 1979; Wilhide and Larcom, Annals Clin Lab Science, 1993) or immunotherapy. In an attempt to improve this type of tests, some sources of variation were identified and analysed, a procedure which resulted in a proliferative response to PHA which correlated with the effect of chemotherapy (Wilhide and Larcom, Annals Clin Lab Science, 1993). However, this correlation was found only after 2 months of treatment. Thus, there is no predictive value in this test as the response to chemotherapy generally is evaluated after 3 months using radiological investigations of the involved metastatic sites. Cheema and Hersh (Cancer, 1971) found the proliferative response to PHA and streptolysin “O” to be suppressed after chemotherapy. Recovery with a significant overshoot compared to pre-treatment values 8-10 days after chemotherapy correlated with tumour regression. In patients with progressive disease the proliferative response remained suppressed. The lymphocyte responsiveness to PHA has been claimed to predict the response to chemo-immunotherapy (Toge et al., Gann, 1979). However, in this study, unusual response criteria were used and there seems to be a considerble overlapping between the responding and not responding patients, thus making monitoring of individual patients difficult. On the contrary, no effect of chemotherapy on the response to PHA could be demonstrated and a clinically useful difference between responders and non-responders was not found by others (Jones et al., Clinical Oncology, 1980).
The difficulty to identify immunosuppression on an individual base in cancer patients by means of mitogen stimulation of PBL is as pointed out above to a large extent due to the great inter-individual variation in these tests. This source of variation as well as those sources described by Wilhide and Larcom (Wilhide and Larcom, Annals Clin Lab Science, 1993) can be avoided by adding drugs or cytokines with the ability of modulating the immunosuppressor activity to the in vitro cultures of PBL. With this procedure the immunosuppressor activity can be identified within the same set up of cultures by using the same preparation of PBL and the same culture medium. Thus, a comparison with the proliferative rate in cultures of PBL from other individuals at other test occasions is avoided. Furthermore, by using comparisons within the same test occasion the effect of autologous serum in the culture medium on the proliferative response and immunosuppressor activity can be analysed. This is of course highly appropriate as serum factors might play a significant role in immunosuppression. In addition, the inappropriate influence of cytokines in pooled human AB serum or fetal calf serum is avoided.
In the study forming the basis for the present patent application immunomodulating drugs (indomethacin, cimetidine and chlorambucile) were added to mitogen (PHA or ConA) stimulated cultures of PBL from patients with renal cell carcinoma. Indomethacin inhibits cyclo-oxygenase and thereby the synthesis of PGE
2
, a substance with several down-regulating effects in the immune system. It is well-known within the art that histamine dependent lymphocytes and lymphocytes particularly sensitive to alkylating agents can have an immunosuppressor activity. The possible occurrence of such suppressor activity in cultures of PBL from tumour patients was therefore analysed by adding an alkylating agent, chlorambucil, or cimetidine—a histamine H
2
receptor antagonist—to the culture medium. Alkylating agents, particularly cyclophosphamide has been used to down-regulate immunosuppressor activity (see below). As the alkylating activity of this drug requires activtion in vivo, mainly in the liver, another alkylating agent, chlorambucil, was used in the PBL cultures in this study.
Immunosuppressor activity in PBL cultures sensitive to indomethacin, alkylating agents or histamine H
2
receptor blockers might identify an immune status which correlates with the response to certain types of immunotherapy. Furthermore, identification of patients with such an immunosuppressor activity might give an opportunity to improve the therapeutic efficacy of immunotherapy since cells with suppressor activity can be eradicated or inhibited by treatment with these immunomodulating drugs.
The effect of addition of indomet
Brumback Brenda G.
Landstinget I Ostergotland
Merchant & Gould P.C.
Wortman Donna C.
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