Great work. My money is still on the wall on whether localized chemotherapy will be as/more effectivr, but you've been as systematic as can be and it's worth a shot to test in humans. Glad you used syngenic models instead of xenografts.
Ive been out of touch in this, could you clarify what is the current scientific consensus on the role of immune responses in chemotherapy efficacy vs. direct killing? How does your approach fit into that model?
Further,Could you comment on the immunogenicity of the tumor model you used to test the drug? It's a cell line from the same strain but it's still a line with probably a ton of mutations. Have to tried to establish tumors with more benign cells (or spontaneous tumor models ) to see if the efficacy can be matched in such scenarios as well?
Thank you for your comments.
With regards to your questions.
On chemo leading to cytotoxic vs immune killing
I am not sure that we have reached the point of a consensus on this. I would say that there is more and more evidence of the involvement of the immune system even with therapies that were considered exclusively chemotherapies. I would suggest looking up the work of Guido Kroemer on immunogenic cell death.
On the CAPAC approach fitting that model
Well, our inclination is that our current knowledge is limited by what can be achieved with our current dosing technologies.
For instance, in the specific case of Doxorubicin, you cannot give more than 75 mg/m2 without significantly endangering a person’s health. Assume that only 1-2% of that dose actually reaches the tumor.
How would you know what 10x that dose at the tumor would do? Also how could you separate the effect on the tumor and the side effects that it causes?
About 20-30 years ago, investigators were experimenting with increasing the dose by 20-30% by providing highly risky interventions such as bone marrow transplant. Not surprisingly those studies showed that the toxicity from the drugs was leading to deaths more quickly than the actual disease, so the efforts were abandoned.
We believe that the CAPAC technology allows one to explore biological effects, including a potential activation of the immune system that we have not been able to explore yet. And that is only talking about a single chemotherapy. Imagine if you could have at your disposal many cancer drugs with different mechanisms of action all working at the tumor site at the same time. The effects could be revolutionary.
With regards to the tumor model
We have used different syngeneic lines (fast growing, slow growing) and they all point in the same direction.
We have not tried yet spontaneous tumor models.
By the way, the efficacy is not matched with that of conventional doxorubicin. The efficacy is surpassed with fewer side effects.
Thanks for the answers. Your model does sound promising, and I see you have gathered as much meaningful information as possible before human trials. Good luck and hope it exceeds expectations!
Ive been out of touch in this, could you clarify what is the current scientific consensus on the role of immune responses in chemotherapy efficacy vs. direct killing? How does your approach fit into that model?
Further,Could you comment on the immunogenicity of the tumor model you used to test the drug? It's a cell line from the same strain but it's still a line with probably a ton of mutations. Have to tried to establish tumors with more benign cells (or spontaneous tumor models ) to see if the efficacy can be matched in such scenarios as well?