Combination of immune checkpoint inhibitors with targeted thorium conjugate treatment
I. The purpose of the experiment/project:
The purpose of this experiment is to investigate mechanisms of immune response activation by antibody-targeted alpha therapy (TAT) in allograft cancer models and effects of combining the TAT with immune checkpoint inhibitors on immune response and tumor growth inhibition.
II. The expected adverse effects on the animals:
Three main adverse effects for the mice in this experiment are ulcerations of the tumors, weight reduction and reduction in white blood cell count. To eliminate the adverse effects, we will daily follow the mice well-being, sacrificing the animals with the first signs of ulcer or 15% weight reduction. White blood cell count didn't lead to any noticeable change in animal well-being. Else, animals will be immediately sacrificed with first signs of distress.
III. The expected scientific benefits or benefits for society:
Anticancer therapy is known to activate multiple processes in the tumor lesions, among others activation of immune response. The immune system present in syngeneic mice allograft models allows us study this initial immune response and ways to enhance it. In this study we aim to evaluate enhancement in immune response following combination treatment with TTC and immune modulating therapy. Combination therapy of known anti-cancer drugs with different molecules effecting immune system lead to multiple new treatment regimes and dramatic increase in patient survival for many types of cancer.
IV. The number of animals and species:
In this study we aim to investigate temporal changes in activated T-cells following treatment with 2 different test items. We will collect tumor tissue, spleen, lymph nodes and blood from 5 mice at each of 3 time points, in total 15 mice per treatment. With 6 treatment groups we would need 15micex6groups=90 mice for sample collection for each study, in total 2studiesx90mice=180 mice. In efficacy part, we will treat 15 tumor-bearing mice in each group, in total 15x6=90 mice for each study. For 2 efficacy studies we will use 2x90mice=180 mice. Take rate for selected syngenic mouse model is around 95%. In total we aim to use (180+180)/0.95+10age-matched control = 390 mice.
V. How will the requirements for 3R be accomplished by the experiment/project:
Multiple in vitro studies were conducted to prove the efficacy and specific killing of selected tumor models, as well as extensive characterization of the models was performed. We have already acquired promising data in the same model, thus we have good knowledge of this model with regards to group size, timing of treatment etc. Technicians conduction the study have long experience with similar studies using well refined techniques.
The purpose of this experiment is to investigate mechanisms of immune response activation by antibody-targeted alpha therapy (TAT) in allograft cancer models and effects of combining the TAT with immune checkpoint inhibitors on immune response and tumor growth inhibition.
II. The expected adverse effects on the animals:
Three main adverse effects for the mice in this experiment are ulcerations of the tumors, weight reduction and reduction in white blood cell count. To eliminate the adverse effects, we will daily follow the mice well-being, sacrificing the animals with the first signs of ulcer or 15% weight reduction. White blood cell count didn't lead to any noticeable change in animal well-being. Else, animals will be immediately sacrificed with first signs of distress.
III. The expected scientific benefits or benefits for society:
Anticancer therapy is known to activate multiple processes in the tumor lesions, among others activation of immune response. The immune system present in syngeneic mice allograft models allows us study this initial immune response and ways to enhance it. In this study we aim to evaluate enhancement in immune response following combination treatment with TTC and immune modulating therapy. Combination therapy of known anti-cancer drugs with different molecules effecting immune system lead to multiple new treatment regimes and dramatic increase in patient survival for many types of cancer.
IV. The number of animals and species:
In this study we aim to investigate temporal changes in activated T-cells following treatment with 2 different test items. We will collect tumor tissue, spleen, lymph nodes and blood from 5 mice at each of 3 time points, in total 15 mice per treatment. With 6 treatment groups we would need 15micex6groups=90 mice for sample collection for each study, in total 2studiesx90mice=180 mice. In efficacy part, we will treat 15 tumor-bearing mice in each group, in total 15x6=90 mice for each study. For 2 efficacy studies we will use 2x90mice=180 mice. Take rate for selected syngenic mouse model is around 95%. In total we aim to use (180+180)/0.95+10age-matched control = 390 mice.
V. How will the requirements for 3R be accomplished by the experiment/project:
Multiple in vitro studies were conducted to prove the efficacy and specific killing of selected tumor models, as well as extensive characterization of the models was performed. We have already acquired promising data in the same model, thus we have good knowledge of this model with regards to group size, timing of treatment etc. Technicians conduction the study have long experience with similar studies using well refined techniques.