In the past five years, therapies targeting the MAPK signaling pathway and a succession of new immunotherapies have dramatically changed the landscape of treatment for advanced melanoma. The checkpoint blockade immunotherapies, which work by impeding immune regulators such as CTLA-4, PD-1 and PD-L1 so that more T cells can be released to fight the disease, have perhaps justly captured the lion’s share of the attention, producing long-term remissions in many patients and recently gaining FDA approvals across several types of cancer.
Unfortunately, as is the case with the targeted therapies, the disease eventually advances or recurs in the majority of patients on checkpoint blockade therapy, while others have limited partial responses and some do not respond at all. Yet others have such serious adverse reactions to the medicines that the melanoma therapy must be stopped and other treatment instituted to correct potentially life-threatening conditions.
Thus, we still need therapies to use in lieu of, or in conjunction with, these revolutionary systemic therapies. Among the alternatives, surgery and radiation therapy remain the staples, and in the right clinical settings, they can be extremely effective, especially for palliation. A less commonly considered approach is intralesional therapy, which is emerging as an increasingly viable and encouraging option. In this issue of The Melanoma Letter, Sanjiv S. Agarwala, MD, provides an incisive review of the strategies developed to date in intralesional therapy for melanoma, including the recently FDA-approved T-VEC and several promising experimental strategies.
As noted by Dr. Agarwala, the FDA’s 2015 approval of T-VEC (talimogene laherparepvec, or Imlygic®) was the first significant salvo fired in the field of intralesional therapy. In patients with inoperable melanoma tumors, direct intratumoral injections of T-VEC, a genetically modified herpes virus, have had notable success in eliminating or shrinking the injected tumors, and in some patients have also eliminated or shrunk uninjected nearby (“bystander”) lesions. This has spurred hope of developing intralesional strategies with broader systemic effects. Dr. Agarwala explores the most exciting of these experimental strategies, including electroporated interleukin-12, CAVATAK (CVA21) and PV-10 (rose bengal). His detailed review of the response rates for both injected and uninjected lesions seen in completed studies and his breakdown of studies to come offer an excellent overview of the promise and remaining challenges in this field.
The advent of increasingly effective but imperfect individual melanoma therapies has paved the way for even more promising combination therapies. In the near future, despite their apparently limited systemic effects as monotherapies, the intralesional therapies may have an extremely important role to play in both potentiating and complementing the systemic therapies.
Allan C. Halpern, MD • Editor-in-Chief
Ashfaq A. Marghoob, MD • Associate Editor