Question: Jazz-Micrbe et. al
First, I appreciate the posts about the background on the MOA of Bavi. I might add to this list a commentary from last weeks NEJM (and follow it with a question):
NEJM, Volume 354:2503-2504, June 8, 2006
A Better Way for a Cancer Cell to Die
Richard A. Lake, Ph.D., and Robbert G. van der Most, Ph.D.
In their recent study of the lethal effects of chemotherapy on cancer cells, Casares et al.1 have shown that, after the fatal blow, cancer cells can take different pathways to death's door, depending on the chemotherapeutic agent used. One of these routes has immunologic consequences with important clinical implications; the other kills the cell without exciting the immune system.1 The experiments, carried out in mice carrying subcutaneous tumors, indicate that if a chemotherapeutic agent kills cancer cells in a way that renders them immunogenic, it has a therapeutic benefit over and above the cytotoxic action of the drug. The study also reinforces the notion that the interaction of dead and dying cells with the immune system can be positive, neutral, or negative.2
[snip]
Every day, billions of normal cells in the body undergo apoptosis; if just a fraction of them were immunogenic, autoimmunity would be a serious problem. Since autoimmunity is not common, this form of apoptosis has been considered nonimmunogenic, or bland. In contrast to bland apoptosis, cell death in the presence of proinflammatory microbial products — such as lipopolysaccharide, unmethylated cytidine–phosphate–guanosine motifs, and double-stranded RNA — triggers a protective immune response. A tumor cell killed by chemotherapy is thought to lack proinflammatory molecules and should therefore elude notice by the immune system. The actual situation, however, is more complex. Apoptotic tumor cells, but not malignant cells in necrotic tumors, can provoke an antitumor immune response.3 Now, Casares et al. refine our knowledge of the situation by showing that not all forms of apoptosis are equal with respect to the immune system. Two drugs — doxorubicin and mitomycin — that bind to DNA and induce apoptosis in tumor cells were used, but the apoptotic cells that were killed by doxorubicin triggered an immune reaction, whereas the apoptotic cells killed by mitomycin did not.
The investigators showed in a mouse model that colon-carcinoma cells (CT26 cell line) that were killed by doxorubicin (an agent that intercalates with DNA) were first taken up by dendritic cells and then induced the proliferation of antitumor cytotoxic CD8+ T cells (Figure 1). These apoptotic cells — killed by doxorubicin — inhibited the growth of small tumors. Furthermore, established CT26 cancer cells regressed after doxorubicin was injected directly into the tumor. These events occurred only when the tumor cells were killed in a caspase 3–dependent manner, which stresses the importance of apoptosis. By contrast, dendritic cells ignored CT26 cells in which apoptosis was induced by mitomycin, and there was no immune response against the cells. The treatment of these mitomycin-killed cells with doxorubicin (which would be expected to be intercalated with the DNA of the newly killed cells) failed to make the cells immunogenic, indicating that the induction of apoptosis by doxorubicin was critical to the outcome.
[snip]
Clearly, further investigation of the immunogenic potential of other chemotherapeutic drugs, both alone and in combination, is warranted. When the administration of chemotherapy results in only weakly immunogenic dead tumor cells, targeted immunotherapy may be an alternative. In fact, immunotherapies aimed at the immune system itself (Figure 1) may be more versatile if they can be used with any chemotherapy, so that for a particular cancer, a clinical trial would test a supplementary protocol added to the current best practice.
End of article.
My question relates to the statement: "Every day, billions of normal cells in the body undergo apoptosis; if just a fraction of them were immunogenic, autoimmunity would be a serious problem."
If you look at the middle picture that appears on this message board presented by Dr. Thorpe indicating the localization of Bavi to the pancreas in a mouse model of pacreatic cancer, it also shows a fair amount of localization in the lungs, where there is a high rate of apoptosis. Why isn't Bavi toxic to normal cells, initiating a cellular immune response and associated inflamation in normal dying cells?
As an aside, if I were the PR people in charge of PPHM, I'd have letter to the editor sent off by now to the NEJM in response to the above article.
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