Saturday, July 23, 2016 3:15:54 PM
Conventional Responses
-- Tumor shrinkage
Immunotherapy Benefit go above and beyond conventional responses. To look only at conventional response rate is faulty as it doesn't give a true picture of response benefit.
They were able to show immunotherapy shows a very unique type of response using :
Clinical Observations for Efficacy, distinctly different for ilpilumumab. In early studies treatment was stopped; as it looked like a low response rate. But as they were following up on data, their clinical benefit curve started much later, showing a prolonged effect and an a mix of conventional and unconventional responses are what ultimately proved efficacy benefit.
---
Immunotherapy introduced into clinical testing under old paradigms.
Drug development new agents under standard treatment testing paradigms:
-- looks at conventional responses (I.e., shrinkage)
-- and those conventional responses were used for signals of activity.
As such the Clinical signals of ilpilumumab:
-- relatively low conventional response rates: (10-15% in melanoma)
But then:
-- they noticed survival improvement more than their response rate initially was suggesting as
That suggested that there must another benefit beyond the conventional response (same observation as other immunotherapies).
In order to identify that "other benefit" more carefully:
They tracked efficacy back:
--- observed mixed response (definitive proof of efficacy, above and beyond conventional)
Mixed Response in immunotherapy
-- some lesions shrink while;
-- other lesion grow
-- new lesion appear while
-- others disappear
MIXED response picture comes from:
Immune editing effect of the immune system:
Relationship with T cell response with the tumor:
Different tumors may have different target antigens;
May have different tumor microenvironment
And therefore:
RESPONSE is not uniform to an immunotherapy intervention. Instead it is a fairly complex pictures, which leads to mixed clinical observation:
Case studies showed mixed examples of efficacy benefit:
1)Includes conventional case study response patterns where after initial treatment the tumors shrink
2) Includes case study response patterns where after initial treatment: Tumors grow, and then subsequently shrink; predominantly because Lymphocytic infiltration into the tumor; makes the lesion larger, for the T cells can then acts against the tumor cells that leads to shrinkage
3) includes case study response patterns where the immune system is the some form of equilibrium state with the tumor ; and leads to prolonged stabilize disease. That may over time lead to a response but it may take time to a year or more for that to happen.
4) includes cases study response patterns where actually new lesions appear while other lesions disappear or shrink. Those patterns are particularly interesting because they suggest that micro metastatic tumor cell deposits in different tissues that once detected by the immune system may actually lead to a visible lesion on a CAT scans, that previously did not exist, because T cells accumulate around the micro metastatic tumor cell and make that a visible lesion. Those lesion are usually small and they are transient. They go away with time, once the T cells do their job.
Diverse immunotherapy case study patterns of efficacy response:
But only ONE of the FOUR benefits would have meet the criteria of the old paradigm of conventional response rates. :)
http://www.blogtalkradio.com/pharmatalk/2015/12/21/immuno-oncology-drug-development-challenges-next-steps
Also goes on to speak about vaccines, mono-therapy and combination therapy. And TCR-t, which NWBio recognizes as a supplementary combination therapy:
http://www.nwbio.com/NWBT_corp_overview_(SMiconf)_9-16-15.pdf
It's a MUST listen to talk.
I hope you recognize DCVax-L and Direct responses in the talk. All skeptics should listen to it. :)
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