Subj: Biological Response Modifiers
Date: 9/2/02 3:32:18 PM Pacific Daylight Time
From: (an oncologist) @aol.com
Can you comment on the use / testing of biological response modifiers in the DiSC Assay? Pro's / Con's?
The DISC assay is the only assay reported to be capable of distinguishing
between specific cytolytic effects on different cell populations in a heterogeneous
mixture of tumor cells and normal cells. The principle is that patients
whose tumors contain endogenous effector cells which respond to cytokine
stimulation by producing tumor-specific cytotoxicity will be more likely
to benefit from cytokine therapy than patients whose tumors do not contain
effector cells capable of being so stimulated.
Note that I do not expect that this assay will be perfect, but it may well be useful, if patients so selected have a higher than expected probability of benefiting from cytokine therapy.
To date, the main line of evidence supporting the biologic validity of this assay is the fact that the in vitro patterns of cytokine activity seen in our assays are quite consistent with known clinical patterns of cytokine activity (see references below). In addition, cytokines are never active in the complete absence of effector cells, but effector cell content does not predict activity, as long as at least some effector cells are present. Tumors with endogenous E:T ratios of 0.1 are no less likely to be "sensitive" to cytokines in the assay than are tumor with endogenous E:T ratios of 5. Tumors with E:T ratios of 0 are, however, always insensitive. Finally, dexamethasone, 1 uM, abrogates cytokine activity in the assay.
We have yet to perform a clinical trial to determine to what extent the in vitro findings correlate with clinical response to cytokine therapies.
A bibliography describing published results with this assay in the study of biologic response modifiers is listed below.
Thank you for your question. Let me know whenever/if ever you have others.
Larry M. Weisenthal, M.D., Ph.D.
DISC Assay Biological Response Modifiers Bibliography
1. Einhorn S, Fernberg J-O, Grand‚r D, Lewensohn R (1988) Interferon exerts a cytotoxic effect on primary human myeloma cells. Eur J Cancer Clin Oncol 24: 1505-1510
2. Lepri E, Barzi A, Menconi E, Portuesi MG, Liberati M (1991) In vitro synergistic activity of PDN-IFNà and NM + IFNà combinations on fresh bone-marrow samples from multiple myeloma patients. Hematol Oncol 9: 79-86
3. Weisenthal LM, Nagourney RA, Kern DH, Boullier B, Bosanquet AG, Dill PL, Messenger JC, Moran EM (1989) Approach to the clinical circumvention of drug resistance utilizing a non-clonogenic in vitro assay measuring the effects of drugs, radiation, and interleukin-II on largely non-dividing cells. In: Amadori D, Ravaioli A, Ridolfi R (eds) Strategies in cancer medical therapy: biological bases and clinical implications (Advances in Clinical Oncology, V.1.). Edimes, Pavia, Italy, pp 91-111
4. Weisenthal LM, Dill PL, Pearson FC (1990) Tumor and patient-specific activity of biologic response modifiers (ImuVert, tumor necrosis factor, alpha-interferon) in fresh specimens of human neoplasms detected by a sensitive and specific in vitro assay. Proc Am Assoc Cancer Res 31: 299(Abstract)
5. Weisenthal LM, Dill PL, Pearson FC (1991) Effect of prior cancer chemotherapy on human tumor-specific cytotoxicity in vitro in response to immunopotentiating biologic response modifiers. J Natl Cancer Inst 83: 37-42
6. Weisenthal LM (1991) Effect of prior chemotherapy on biologic response modifier activity. J Natl Cancer Inst 83: 790-791
7. Weisenthal LM, Dill PL (1992) In vitro effect of interleukin-2 on fresh human tumor cell cultures measured by the DiSC assay. Proc Am Assoc Cancer Res 33:Abs 3313
Best Methods-Type Publication relating to the DISC assay for biologic response modifiers, with color photomicrographic illustrations (the paper also reported I think interesting findings, which have never received the follow-up they deserve) ->
6: J Natl Cancer Inst 1991 Jan 2;83(1):37-42 Effect of prior cancer
chemotherapy on human tumor-specific cytotoxicity in vitro in response
to immunopotentiating biologic response modifiers.
Weisenthal LM, Dill PL, Pearson FC.
Tumor-specific cytotoxicity was measured in fresh human biopsy specimens by a modification of the differential staining cytotoxicity assay. ImuVert, a cytokine inducer derived from Serratia marcescens, which produces broad-spectrum activation of both macrophages and lymphocytes, was dramatically more effective when it was tested in tumors obtained from patients with previously treated, chemotherapy-responsive adenocarcinomas (breast and ovary) than when it was tested in tumors obtained from either previously untreated patients or previously treated patients with chemotherapy-refractory adenocarcinomas (colon, lung, pancreas, stomach, kidney, gallbladder, uterus, and prostate). Similar findings, relating to prior chemotherapy treatment status, were obtained for tumor necrosis factor and interferon gamma, but not for interleukin-2 or interferon alpha. On the basis of these findings and on other evidence in the literature, we speculate that response to chemotherapy produces massive release and processing of tumor antigens. We further speculate that this response leads to a state in which the human immune system is primed (via in situ vaccination) to respond to exogenous macrophage-activation signals with potent, specific antitumor effects.