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Screening for chemoimmunotherapeutics, success rate and predictivity of models: a five years experience
Abstract:
While repository adjuvants are already established drugs for antigen specific immunomodulation, no unspecific active immunomodulator has successfully passed clinical trials in tumor patients in western countries yet. As this is in striking contrast to the effects seen with unspecific immunomodulators in experimental immunological and tumor test systems, the value of those screening models to predict clinical success may be asked for. To improve the success rate, it is recommended to test compounds for their immunomodulatory effects as broad as possible in ex vivo and in vivo test systems. Subsequently, the prophylactic as well as therapeutic potency of selected immunomodulating drugs should be evaluated in various models of aptitude, such as chronic infection, autoimmune diseases and chronic inflammatory reactions. Those diseases are at least to a certain extent influenced by the immune system, in contrast to the uncertainty in case of tumor diseases. In a battery of chronic infection models we could find that different chemoimmunotherapeutics with very similar immunopharmacological activity behaved quite differently. Most compounds were ineffective, a part enhanced chronic diseases and only in a few cases a therapeutic effect could be shown. On the other hand, effectivity in protection against the pathogenicity of subsequently applied, selected microorganisms does not predict the therapeutic potency for the same pathogen. Altogether the data show that activation of cells of the immune system by an immunostimulating drug does not predict its therapeutic potency. Moreover, activation of immune cells may also lead to impairness of the immune resistance.
Insights
Unspecific immunomodulators show promise in lab tests but often fail in human cancer trials. Activating immune cells does not guarantee therapeutic success, highlighting the need for better predictive models in drug development.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Antigen-specific immunomodulators are established, but unspecific immunomodulators have not succeeded in Western clinical trials for cancer.
- Experimental models show promise for unspecific immunomodulators, contrasting with clinical trial outcomes.
Purpose of the Study:
- To evaluate the predictive value of experimental models for clinical success of unspecific immunomodulators.
- To investigate the efficacy of immunomodulating drugs in various disease models beyond cancer.
Main Methods:
- Compounds were tested for broad immunomodulatory effects in ex vivo and in vivo systems.
- Prophylactic and therapeutic potency were evaluated in chronic infection, autoimmune, and inflammatory disease models.
- Chemoimmunotherapeutics with similar immunopharmacological activity were compared in chronic infection models.
Main Results:
- Most tested compounds were ineffective in chronic infection models; some worsened disease, and few showed therapeutic effects.
- Efficacy in protecting against pathogens did not predict therapeutic potency against the same pathogen.
- Activation of immune cells by immunostimulants did not correlate with therapeutic potency and could impair immune resistance.
Conclusions:
- Current experimental models may not accurately predict the clinical success of unspecific immunomodulators in cancer.
- Broader testing in diverse disease models is recommended to improve the success rate of immunomodulatory drug development.
- Immune cell activation is insufficient to predict therapeutic efficacy and may sometimes be detrimental.