Sunday, 10 May 2015

Keytruda / Opdivo lung cancer antibody drug - How does the latest FDA approved cancer immunotherapy (pembrolizumab / MK-3475) for melanoma "cure" some advanced lung and bladder cancer patients?

New melanoma antibody drug Keytruda (pembrolizumab / MK-3475) demonstrates utility in advanced lung and bladder cancer patients

Antibodies, such as Keytruda, that target T-cell inhibitory / checkpoint pathways are emerging as an important class of cancer therapeutics. Keytruda along with Opdivo and Yervoy are the first examples of these next generation immunomodulatory therapies which target inhibitory pathways; PD-1 and CTLA-4 respectively. Alternative inhibitory pathways currently being developed include the B7-H4, B7-H3, TIM-3, LAG-3, VISTA, while antibodies targeting co-stimulatory pathways are also actively being pursued (e.g. CD27, CD137, GITR, OX40).

Preclinical research as well as preliminary data from clinical studies suggests that targeting these immune system checkpoint pathways can induce long term / durable clinical responses in patients suffering from a variety of tumour types other than melanoma, including, lung, bladder, and colon cancer.

Keytruda Pembrolizumab - MK3475, Merck - MSD picture - antibody binding PD-1 during T-cell activation and how these antibodies down regulate inhibitory T-cell signaling which stimulates relatively tumour specific T-cell activation

Other cancers that may benefit from these treatments based on their high PD-L1 cell surface expression levels include:

  1. Glioblastoma/mixed glioma 
  2. Nasopharyngeal cancer  
  3. Hepatocellular carcinoma  
  4. Urothelial cancer  
  5. Multiple myeloma 
  6. Ovarian cancer  
  7. Gastric carcinoma 
  8. Esophageal cancer 
  9. Pancreatic cancer 
  10. RCC
  11. Breast cancer
  12. Lymphomas
  13. Leukemias
  14. Prostate cancers – The suggestion that prostate cancers may benefit from this therapy comes with a caveat though, given that PD-L1 has only been reported in approximately 1% or less of prostate tumour samples. However, one study found that although prostate cancer lesions were PD-L1-negative (i.e. do not express this protein on their cell surface), they were surrounded by clusters of PD-1-positive and PD-L1-positive immune cells (lymphocytes). This observation fits well with the notion that low PD-L1 expression levels on tumour cells do not automatically preclude a positive response to PD-1 antibody treatment (as per clinical trial observations in other types of cancer).
Nevertheless, in order to explain PD-1 antibody (Keytruda) development and its use as a lung cancer treatment, it is perhaps important to first understand how this antibody initially evolved. So please indulge me briefly, while I explain to you an important hallmark of cancer (which is exploited by this PD-1 antibody therapy) and the melanoma aspect before I move on to anti- PD-1 antibody utility in late stage lung cancer patients and a list of current clinical trials.

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