Thursday, July 31, 2014

With Anti-PD1, and Ibrutinib, we have entered the new world of therapy in cancers

The time of dirty bomb that standard Chemotherapy represented, has quickly led to major side effects and of course given us partial results.  Cure was not achieved most of the times except in rare chemotherapy successes such as in Hodgkin disease and some cases where disease was limited, and surgery with adjuvant chemotherapy plus or minus Radiation allowed the cancer patients to survive.   Even in these rare cure cases, Doctors remained on the look-out using Biomarkers that most of the time "only God knows "worked.  Recurrences and secondary cancers were clearly unpredictable and random, we could not come up with decent explanation, except for a conclusion that the earlier therapeutic intervention may have precipitated them or have something to do with them.

Today, with our increasing knowledge of cellular pathways, we live one step forward, an exciting time in Oncology and hematology/Immunology/Rheumatology.  The discovery that target therapy unveils new cures has the Oncology community bubbling with excitements (at least they (Oncologists) should!).   We are now tackling newly cancers such as Melanoma and refractory lung cancers with further excitement then before.  Indeed we are curious to know whether the promise of target therapy will be achieved in every new cancers we encounter.   We suspected without clear knowledge that Target therapy would work since the effect of IL-2 in renal cancer has never been matched by standard chemotherapy, and the striking fact that only high dose Interferon worked in adjuvant treatment of Melanoma.   Furthermore, our suspicion was that these agents were acting by boosting the immune system against cancer cells.  No need to say or emphasize that this effect was so profound that cure was achieved in some difficult cancers.  Our limitations and fear to pursue this line of attack against cancer cells were mainly limited because of the unexpected side effects (the vascular disturbance and resulting extravasation syndrome induced by these agents at high dose).   And it acted as a Dirty bomb by overwhelming the cancer cells hidden paths to Apoptosis.  Today however, we have gotten smarter hitting check point targets "at will" and more "surgically".   And Oncologists have become a little abrasive and more confident.  Expression such as "Up front, hit hard, and don't stop" is being published (Sandra Ker) about the use of Target therapies!   The surprising effect of anti-PD-1/ PDL1 and their relative lack of dramatic side effects is a feast we should enjoy!   Are they the receptors stimulated non-specifically by these previous high dose Interleukin-2 and Interferon...research is underway to figure that one out with certainty.  But already combining these old strategies (IL-2, Interferon) with the new Ibrutinib and Nivolumab is on the mind of researchers to try to tease the new unveiled therapeutic concepts.

Many (include this authors) believe that  the success of the AntiPDL-1 actually lies in a well known concept that, on a daily basis, cells that go awry end up being removed from our system by the army of white blood cells that we have, and this is why the cancer cells will work hard to hide themselves from the Lymphocytes.  The discovery of ways to activates the White Blood cells against tumors seem to offer a winning approach in cancer management and therapy!    The approaches tackling PD-1, PDL-1, and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), all seem to work...When in Breast cancer lymphocyte infiltration seems to predict response to chemotherapy, we know another "volet " (french for compartment) is being unveiled in the story of White blood cells and cancers!

One thing for sure, and clearly another challenge to confront now, is the build up of escape mechanisms against these new therapeutic avenues.  We have come to realize, that we can't tell cells including cancer cells that it is alright to die now!  Cancer cells like all cells continue to figure that our therapeutic interventions are a new "environmental" challenge and continue to figure new escape mechanisms (pathways to resistance cancers) forcing us to have to design a multiple step strategy to achieve the cure.  Indeed "2 or multiple punches" strategy is needed sometime to achieve longer progression free survival or Overall survival (OS) by sequencing or concurrently using available drugs!   But now that is another "Volet".....CRBCM is hard at work!
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