Monday, June 6, 2016

ASCO 2016 - Measuring T-cell exhaution to predict response to anti-PD1 vs ipi/nivo increases and delayed increases in CD4+ and CD8+ T cells = positive outcomes with ipi

Finding a marker...of any sort....than can be tested easily and evaluated predict response to therapy would be an amazing leap forward in melanoma treatment.  I have looked at what researchers are exploring before here:  Biomarkers: blood components, circulating tumor cells and the tumor itself  
Now there is this:

Novel T cell exhaustion marker to predict monotherapy PD-1 compared to combination CTLA-4 and PD-1 response in melanoma.  ASCO 2016.  #9520.  J Clin Oncol 34, 2016.  Loo, Tsai, Pauli, et al.

Background: The identification of a robust biomarker to determine potential responses to checkpoint mono- or combination therapy is critical in order to stratify patients and rationally select therapy. We explored the utility of proportion “exhausted” antigen experienced T cells (TEx)/Total CD8+ cells to predict response. Methods: Freshly isolated tumor samples were digested and tumor infiltrating lymphocytes (TILs) were extracted and stained with T cell myeloid and activation markers, and analyzed with 14 color FACS. Patients were treated with the combination therapy Ipilimumab 3 mg/kg q3 week x 4 and Nivolumab 1 mg/kg q3 week (Ipi/Nivo), or monotherapy of either Nivolumab 3 mg/kg q2 week or Pembrolizumab 2 mg/kg q3 week. TEx was calculated as % CD8+, PD-1+, CTLA-4+ cells divided by total CD8+ T cells in the tumor sample. Results: A total of 53 patients were evaluable for both response and T cell phenotype, 15 patients were treated with combination Ipi/Nivo, and 38 with monotherapy PD-1. For monotherapy, 0/12 (0%) responders had a TEx less than/= to, 20%, while 21/26 (81%) of the responders had a TEx greater than 20%. For responders, median TEx = 40.3%, for non-responders, median TEx = 16%,. At this threshold, the negative predictive value (NPV) was 100% and the positive predictive value (PPV) was 81%. For patients treated with combination Ipi/Nivo, the threshold for response was much lower. Responses to the combination therapy were seen at all levels with NPV=50% and PPV=80%, with responders median TEx = 19.7% and non-responders median TEx = 7.8%. Conclusions: Comprehensive tumor T cell profiling with FACS reveals interesting insights into tumor response to checkpoint inhibitors. % TEx is an accurate predictor of response to monotherapy but not combination checkpoint therapy. Combination Ipi/Nivo therapy produces responses at a much lower TEx threshold, suggesting enhanced rescue and/or recruitment of T cells into the tumor microenvironment. 

% TEx
Monotherapy PD-1, ORR
> 20%
Ipi/Nivo, ORR

Believe it or not...this bunch of mess makes common sense.  If a group of people with melanoma have very exhausted t cells...that means that those cells have been fighting the beast, but have become worn out doing so.  Giving them a treatment that boosts t cell anti-PD1...will more likely be effective for them rather than for those whose t cells were still active and NOT tired...just not effective against their melanoma.  However, this was true only for the administration of anti-PD1 monotherapy, the difference was not as striking when patients were given the ipi/nivo combo...probably due to the fact that ipi works much earlier in the immune response cycle by helping recruit the initial response. So....this could be helpful in deciding which patients would glean the most benefit from the combo, despite its potential side effects, as opposed to those who would be benefited by anti-PD1 alone. Look at the graph above.  When greater than 20% of your t cells are worn out, you get an 80% of a chance of a response to anti-PD1 alone...which is the same for the t cell exhausted folks who took the combo.  BUT!  If your cells were NOT exhausted, you have a 0% chance of response to anti-PD1 alone, but a 50% chance of response to the ipi/nivo combo.

This next study follows other work done to determine what peripheral blood markers are associated with what outcomes in patients who have taken ipilimumab...some of the work by some of the same peeps with links to other info is here:  Blood markers associated with clinical outcomes with ipi

Increases in absolute lymphocytes and circulating CD4+ and CD8+ T cells are associated with positive clinical outcome of melanoma patients treated with ipilimumab.  Martens, Wistuba-Hamprecht, Yuan,...Wolchok, et al.  Clin Cancer Res. 2016 May 11.

[This study was done] to investigate changes of peripheral blood biomarkers and their impact on clinical outcome following treatment with ipilimumab in advanced melanoma patients.

Changes in blood counts and the frequency of circulating immune cell populations analyzed by flow cytometry were investigated in 82 patients to compare baseline values with different time-points after starting ipilimumab. Endpoints were overall survival (OS) and best clinical response. Statistical calculations were done....

Increases in absolute lymphocyte counts (ALC) 2-8 weeks and in percentages of CD4+ and CD8+ T cells 8-14 weeks  after the first dose of ipilimumab were correlated with improved survival. These associations did not meet significance criteria, when conservatively adjusted for multiple testing but were additionally correlated with clinical responses. However validation is required. Increases in all three factors were observed in 36% of patients, who had a favorable outcome and survival probabilities of 93.3% and 63.8% at 12 and 24 months, respectively. A partial or complete response was observed in 71% of these patients compared to only 8% in patients with decreases in {greater than or equal to}1 of the 3 factors, respectively. Changes of regulatory T cells (Tregs) or myeloid-derived suppressor cells (MDSCs) were not associated with OS.
Increases of ALC observed 2-8 weeks after initiation of ipilimumab and delayed increases in CD4+ and CD8+ T cells reflect changes associated with positive outcome. These changes represent surrogate marker candidates and warrant further validation.

This is only applicable to ipi, but is a more readily available blood test than the evaluation noted in the prior study.

My brain is tired.  Thanks for your brain power, B!! Best - c

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