Immune Checkpoint Blockade Sparks Optimism in Fight Against Melanoma and Other Cancers
Close examination of the cell and molecular biology of cancer has yielded a raft of new compounds to supplement or replace long-established approaches via some combination of surgery, radiotherapy and cytotoxic chemotherapy. These drugs, illustrated for advanced melanoma in Table 1, include attempts to counter the ability of cancer cells to evade immune attack. These developments have been rapid, and earlier this year one expert said that in five to 10 years’ time more than 50% of cases of advanced melanoma might be curable, conceding that if he had made the statement five years ago, “people would have said I was completely mad.” Not everyone will be quite so optimistic, but there is no denying the excitement among skin-cancer specialists.
Space constraints mean that only one mechanism can be covered this time around, and I have chosen checkpoint blockade, consulting the Web of Science for new reviews along with recent clinical trials that are already accruing citation totals.
A selection of drugs, old and new, used in or under development for the treatment of advanced melanoma
|Alkylating agent||dacarbazine, temozolomide|
|BRAF inhibition||vemurafenib, dabrafenib, sorafenib|
|MEK inhibition||trametinib, selumetinib, cobimetinib|
|Tyrosine kinase inhibition||imatinib, dasatinb, sunitinib|
|PKC inhibition||enzastaurin, sotrastaurin|
|Checkpoint blockade||ipilimumab, nivolumab, BMS-936559, lambrolizumab|
|Plasmid DNA attack||velimogene aliplasmid|
|Modified virus attack||talimogene laherparepvec|
|*Agents shown in bold type are covered in this or earlier editions of ScienceWatch|
Cancer cells ought to be treated by the body as foreign, but it has not proved easy to target tumors by harnessing patients’ immune systems. For one thing, these aberrant cells have ingenious ways of getting round immune defenses. Checkpoint blockade is molecular pharmacology’s counter to that ingenuity. The drug ipilimumab targets cytotoxic T-lymphocyte antigen-4, while other targets are programmed cell death (PD) receptor using the IgG4 antibodies nivolumab (BMS 936558) and lambrolizumab (MK-3475) and the ligand PD-L1 (BMS-936559). Nivolumab was included among ten “antibodies to watch in 2013” (J.M. Reichert, mAbs, 5: 1-4, 2013) and (with BMS-936559) is deemed to have “changed the landscape in oncology in 2013” (C. Robert, et al., Eur. J. Cancer, 49:2968-71, 2013), verdicts justified by the large number of trials still recruiting and by early experience in advanced melanoma (Table 2). Melanoma is by no means the only indication under study with this drug (e.g., renal cell carcinoma).
Selected, recent papers (reviews and clinical trials)
on anti-PD1/PD-L1 agents in advanced melanoma
|A.M. Menzies, G.V. Long, “New combinations and immunotherapies for melanoma: Latest evidence and clinical utility,” Ther. Adv. Med. Oncol., 5(5): 278-85, September 2013.
[U. Sydney, Australia]
|D.B. Page, et al., “Checkpoint modulation in melanoma: an update on ipilimumab and future directions,” Curr. Oncol. Rep., 15(5): 500-8, October 2013. [Memorial Sloan Kettering Cancer Ctr., New York, NY]|
|R.J. Sullivan, P.M. LoRusso, K.T. Flaherty, “The intersection of immune-directed and molecularly targeted therapy in advanced melanoma: Where we have been, are, and will be,” Clin. Cancer Res., 19(19): 5283-91, 1 October 2013. [Harvard U., Boston, MA; Wayne St. U., Detroit, MI]|
|J.R. Brahmer, et al., “Safety and activity of anti-PD-L1 antibody in patients with advanced cancer,” New Engl. J. Med., 366(26): 2455-65, 28 June 2012. [11 US institutions]
Times cited: 291
|S.L. Topalian, et al., “Safety, activity, and immune correlates of anti-PD-1 antibody in cancer,” New Engl. J. Med., 366(26): 2443-54, 28 June 2012. [15 US institutions]
Times cited: 383
|J.S. Weber, et al., “Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab—refractory or—naive melanoma,” J. Clin. Oncol., doi: 10.120/JCO.2013.51.4802. [Moffitt Cancer Ctr., Tampa, FL; Bristol-Myers Squibb, Princeton, NJ]|
|J.D. Wolchok, et al., “Nivolumab plus ipilimumab in advanced melanoma,” New Engl. J. Med., 369(2): 122-33, 11 July 2013. [6 US institutions]
Times cited: 27
|SOURCE: Thomson Reuters Web of Science
[Note: papers not showing citation totals had not yet accrued any in Web of Science as of early December 2013]
Two papers in Table 2 (Brahmer, Topalian), published in mid-2012, have already accumulated a combined 674 citations, yet both of them (and Weber too) are phase 1 trials in patients with various cancers, including melanoma.
The Topalian et al. paper, in fact, according to bimonthly citations tracked in the Hot Papers section of Thomson Reuters Essential Science Indicators, is currently the most-cited medicine paper published in the last two years (aside from reviews), based on citations tabulated during July-August of 2013. The paper registered nearly 90 citations during that two-month period.
In Brahmer et al., nine of 52 patients (17%) assessed for efficacy achieved objective responses, complete in three. In Topalian et al., the objective response rate was 28% (26/94).
A former deputy editor of The Lancet, David W. Sharp, M.A. (Cambridge), is a freelance writer living in Minchinhampton, Gloucestershire, UK.
The data and citation records included in this report are from Thomson Reuters Web of KnowledgeSM. Web of KnowledgeSM is a registered trademark of Thomson Reuters. All rights reserved.