This week Nature Medicine published new study that suggests that Cetuximab (Erbitux), a chimeric monoclonal antibody directed to the EGFR, induces immunogenic cell death in susceptible cancer cells that carry wild-type form of oncogene KRAS.
Nowadays such research articles are common. Cancer immunotherapy really took off in the past 3 years and many want to jump on the immunotherapy bandwagon. However, I selected this paper for review for entirely different reason. I wanted to highlight how science behind Cetuximab was so advanced and ahead of its time [when it was originally tested] that it deemed ineffective [due to some data inconsistency for reasons that became known only later].
Let me remind you that Cetuximab was originally developed and tested by the biotech company called Imclone in 1990s. In clinical trials it was effective in ~20% of patients. However, trials were poorly designed [some did not even show effect] and when FDA refused to accept Imclone's submission for Cetuximab approval in December 2001, company collapsed and its CEO, Samuel Waksal, went to jail for insider trading.
In retrospect, we can now [based on this new paper] reconstruct to what happened to Cetuximab's original trials. This analysis, in my opinion, clearly vindicates Imclone's and Samuel Waksal's scientific approach, at that time, to explain Cetuximab trials.
The 1st finding from this new study was that mice injected with Cetuximab-treated hEGFR-CT26 cells, a mouse colorectal cancer cell line (mCRC) expressing human EGFR, are protected against secondary challenge with parental CT26 cancer cells. This suggested that Cetuximab treatment of CT26 cancer cell induced immunogenic cell death (F stands for FOLFIRI, a standard chemotherapy regimen for mCRC that does not induce immunogenic cell death. FT stands for freeze-thaw).
The 2nd finding was that Cetuximab + FOLFIRI induced immunogenic cell death in human cancer cells with
(a) wild-type forms of oncogenes KRAS and BRAF or
(b) with KRASG13D and KRASG12D mutations
(b) with KRASG13D and KRASG12D mutations
(c) but it did not induce immunogenic cell death in cancer cells with with BRAF and KRASG12V mutations. In those cell lines immunogenic cell death could be restored by combining Cetuximab + FOLFIRI with inhibitors of mutated BRAF (PLX4032, PLX) and MEK (trametinib, tram).
In summary, these data define molecular markers that make cancer cell susceptible to Cetuximab + chemotherapy combination.
Now lets go back to Imclone's story. At the time of original trials, in late 90s, patients stratification based on tumor genetic makeup was a novel idea and not all mutations were known. In fact, when Imclone's management suggested to conduct trial based on patient stratification, European Medical Agency (FDA equivalent in EU) refused to consider it, such unorthodox and unheard of idea it was at that time.
We can now understand why Cetuximab's original trials gave inconsistent results. Without patient stratification, antibody-based therapy rarely shows statistically significant benefits over placebo in cancer patients. Science behind Cetuximab was so ahead of its time that clinical trials were not ready for it and neither were Imclone's management (note that few years later after Imclone's debacle Cetuximab was approved by FDA and it is marketed by Bristol-Myers Squibb).
David Usharauli
Now lets go back to Imclone's story. At the time of original trials, in late 90s, patients stratification based on tumor genetic makeup was a novel idea and not all mutations were known. In fact, when Imclone's management suggested to conduct trial based on patient stratification, European Medical Agency (FDA equivalent in EU) refused to consider it, such unorthodox and unheard of idea it was at that time.
We can now understand why Cetuximab's original trials gave inconsistent results. Without patient stratification, antibody-based therapy rarely shows statistically significant benefits over placebo in cancer patients. Science behind Cetuximab was so ahead of its time that clinical trials were not ready for it and neither were Imclone's management (note that few years later after Imclone's debacle Cetuximab was approved by FDA and it is marketed by Bristol-Myers Squibb).
David Usharauli
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