Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Immunotherapy

Posts tagged ‘Immune Checkpoint Inhibitors’

The Science of PD1 PDL1 Cancer Immunotherapy

Nature Cover Checkpoint InhibitorsIn a landmark publication today, the prestigious journal Nature includes five “Letters” regarding checkpoint blockade of the programmed death-1 (PD-1) receptor and its ligand PD-L1. It confirms the promise and potential of the emerging field of immuno-oncology to provide durable and long lasting responses in many cancers.

Readers of the blog will already have read about the stunning early data presented at ASCO this year for the engineered humanized antibody MPDL3280A (Genentech/Roche) in urothelial bladder cancer (UBC). In his Nature Letter, Thomas Powles (Barts) and colleagues sum of the significance of this data in the opening sentence:

“There have been no major advances for the treatment of metastatic urothelial bladder cancer (UBC) in the last 30 years.”

On the basis of this data, MPDL3280A received Breaththrough Therapy Designation from the FDA earlier this year.

Roy Herbst (Yale) and colleagues in their Nature Letter write about biomakers of PD-L1 inhibition and how their data “suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is reinvigorated on antibody treatment.”

At the recent annual meeting of the Society for Immunotherapy of Cancer (SITC), Dr Herbst gave one of the best presentations of the meeting, in which he discussed “Personalized Immunotherapy for Non-Small Cell Lung Cancer.”  His top ten lessons learned kept the audience’s attention throughout.

Tomorrow is the Thanksgiving holiday in the United States, so this will be the only post this week. Thanksgiving is a good time to take a moment out of the hectic life we all live to “smell the roses” and express gratitude for all the positive things around us.

Next week sees the start of the American Society of Hematology (ASH) annual meeting in San Francisco. The cancer conference circuit seems to roll quickly from one meeting to the next at the moment. There’s a lot of promising data, and while we can’t discuss the data before the meeting due to ASH embargo restrictions, next week we will be highlighting some of the presentations we are particularly looking forward to.

Happy Thanksgiving!

Subscribers can login to read more detail about all five Nature Letters, and their implications for the emerging field of immuno-oncology.

 

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Combination strategies for nivolumab in Renal Cell Carcinoma

In her ASCO Gastrointestinal Cancer symposium (ASCO GI) keynote presentation earlier this year, Elizabeth M. Jaffee MD described the future of immunotherapy as being in combinations.

Overcoming or delaying resistance mechanisms or hitting multiple targets to greater effect will be achieved through combinations of drugs rather than single agent therapy. Combination strategies are the accepted future, whether drug companies like it or not.

In her keynote, Dr Jaffee also likened the revolution in immunotherapy to the same excitement the Beatles brought to music or the same magnitude of technology advances made by Apple. We agree completely.

Thought leaders at ASCO expressed similar sentiments. Steven O’Day (UCLA) said,

“This is truly a brave new world of immunotherapy. I think the message is that the revolution is here, it’s ongoing, and it’s bursting out of melanoma into solid tumors.”

Interestingly, no immunotherapy data was considered to be of worthy of presentation in the plenary session at ASCO this year for the second year running, a decision that may reflect either an unwillingness to showcase early data, however good it may appear to be, or the influence of politics on the selection committee.

One potential combination is to target more than one checkpoint pathway to see if you can obtain a synergistic response. This is the rational for combining the monoclonal antibody ipilimumab and nivolumab. Ipilimumab (Yervoy) targets the CTLA-4 checkpoint protein that prevents dendritic cells from priming T cells to recognize tumors while nivolumab targets the PD-1 checkpoint protein that prevents T cells from attacking cancer cells. Yervoy is an FDA approved therapy for the treatment of metastatic melanoma.

Data published last year in The New England Journal of Medicine by Wolchok et al, showed that combining ‘ipi’ with ‘nivo’ gave more frequent and deeper responses in melanoma, but at the expense of much greater toxicity. Some 53% of patients receiving concurrent treatment had a grade 3-4 adverse event (see Table S-1B in the article).

Does it make sense to combine two immune pathway modulating agents? Does the enormous potential for synergy outweigh the additional toxicity? 

To learn more about these insights, log-in for our analysis of the data on nivolumab in renal cell carcinoma (RCC) presented at ASCO 2014.

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