Freitag, 30. Januar 2015

Recent advances in cancer treatment: immune checkpoint therapy, electromagnetic therapy

From time to time I like to highlight biomedical advances that caught my interest. Here are two recent examples:

Immune checkpoint therapies were first applied to advanced melanoma and, as far as I know, they were the first treatment to significantly improve the prognosis of this once intractable cancer (1, 3):
...immune checkpoint antibodies are clinically active in a variety of malignancies, including those not traditionally classified as immunogenic, such as non-small-cell lung cancer (NSCLC)....
Anti-CTLA-4 agents: ipilimumab and tremelimumab...
the number of long-term survivors exceeded the number of patients with objective responses (ORs)...immune-based therapies may generate a sustained antitumour effect in a subset of patients, long after completion of active therapy
Antitumour responses with immunotherapies are heterogenous: responses may be mixed or delayed, lesions may enlarge before shrinking, lesions may remain stable or slowly regress over time. These responses can be potentially explained by T-cell activation and tumoral infiltration by immune cells, as well as intra-patient heterogeneity of tumour–host interactions.
I always thought that a vaccine type immunotherapy would be first to market, but it turned out differently. According to a talk by James Allison I recently went to, longer term data will become available soon.

Tumor Treating Fields (TTFields) 
I admit normally just reading these words I would have to think of quackery, as scam artists really like to abuse the concepts of waves, oscillations and so on, but this is what seems to be a  legitimate treatment. A recent phase III study corroborates claims of efficacy for this innovative and odd therapy for glioblastoma, a type of brain cancer:
"Tumor Treating Fields (TTFields) are an anti-mitotic, physical  treatment modality that acts in metaphase, anaphase and telophase. The NovoTTF- 100A System (NovoTTF), a home-use medical device that delivers TTFields to the  brain, is an established monotherapy for recurrent glioblastoma (GBM)...The trial met its primary and main secondary endpoints, and was closed to accrual after this interim analysis. Adjuvant TMZ chemotherapy and NovoTTF provides a clinically and statistically significant improvement in progression-free and overall survival, and should become the new standard of care against GBM.  "

"The patients were randomized 2:1 to NovoTTF and temozolomide (210 patients) or temozolomide alone (105 patients). The median progression-free survival with NovoTTF was 7.1 months vs 4 months for temozolomide alone, for a hazard ratio (HR) of 0.63 (P = .001). Median overall survival was also better with NovoTTF, at 19.6 months vs 16.6 months, for a HR of 0.75 (P = .034). This translated to 24-month survival rates of 43% in the NovoTTF group and 29% for the temozolomide group."
A new standard of care for this extremely difficult to treat cancer? That is almost too good to be true and the mechansims appears obscure (but see ref. 4a, 4b). Interestingly, the therapy was approved by the FDA in 2011 before there was convincing evidence of benefit over the standard of care. Instead, they demanded mandatory follow-up efficacy studies. At least superficially, this is a good example of highly effective fast-track approval, but I am no expert on this process. Nonetheless the FDA is often accused of being too slow, which I am not sure is justified.

Summary: it's all about the money

Given enough resources science can explore all these fantastic ideas, and sometimes highly speculative ideas turn out right.We just don't understand biology well enough and we need plenty of resources to test ideas. From Helicobacter Pylori, over superresolution microscopy to RNAiAny sufficiently advanced technology is indistinguishable from magic.  Most (many?) inventions appear obvious and elegant only in retrospect.

1. Immune modulation for cancer therapy
British Journal of Cancer (2014) 111, 2214–2219. doi:10.1038/bjc.2014.348

2. (German)
"Interim Analysis of the EF-14 Trial: A Prospective, Multi-center Trial of  NovoTTF-100A Together With Temozolomide Compared to Temozolomide  Alone in Patients with Newly Diagnosed GBM"


3. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369(2): 122–133.

4a. Expert Opin Investig Drugs. 2011 Aug;20(8):1099-106. doi: 10.1517/13543784.2011.583236. Epub 2011 May 9. Tumor treating fields: concept, evidence and future. Pless M1, Weinberg U.

4b. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10152-7. Epub 2007 Jun 5.
Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors.
Kirson ED1, Dbalý V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y.

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