Complete article now available at ncbi.nlm.nih.gov
Most of this is old hat to IV members, but it's in the peer-reviewed repository at ncbi.nlm.nih.gov
Use the link below:
What Started as a Trickle Has Become a Flood, Despite Some Daunting Adverse Effects; New Drugs, Indications, and Combinations Continue to Emerge
Excerpt with PV-10 references:
The harder treatment decision comes, Dr. Weber said, in the two-thirds of patients with more indolent disease. Currently they are likely to receive a single-agent PD-1 inhibitor when treated by community-based oncology practitioners. But the clinical trials assessing up-front combinations of a PD-1 inhibitor with an agent that suppresses Tregs and MDSCs may present other options.
Dr. Weber noted that among the most promising and potent agents in development is OX40 (AstraZeneca), a costimulatory receptor that potentiates T-cell receptor signaling on the surface of T lymphocytes. It is activated by specifically recognized antigens. Curtis et al.20 observed that “OX40 engagement by ligands present on dendritic cells dramatically increases the proliferation, effector function, and survival of T cells.” They showed in a phase 1 study that one course of an anti-OX40 monoclonal antibody induced regression of at least one metastatic lesion in 12 of 30 patients.
Dr. Weber added that pembrolizumab with peginterferon is “actually looking quite promising” and that his phase 1b trial of peginterferon with ipilimumab had an excellent response rate among patients with unresectable melanoma.21 “So old interferon may actually increase the influx of T cells into the tumor and in some cases convert a cold tumor into a hot tumor—which makes it more susceptible to immunotherapy,” he explained. That ability makes interferon a potential partner for checkpoint inhibition. But as adjuvant therapy, Dr. Weber commented, “it will fade out—I don’t see a big role.”
Safety and Tolerability Issues
The PFS benefits of combining one of the newer PD-1 agents with ipilimumab come with a price in toxicity beyond the comfort level of some clinicians, Dr. Weber underscored. “It is significantly more toxic, and dealing with the side effects is a lot of work for the physicians, although the right training and some level of experience managing them can make a difference. It’s worth exposing the patients to the side effects if there is a major augmentation in survival—but we don’t know that yet.”
Many clinical trials are evaluating PD-1 inhibitors in combination with one or more agents, Dr. Weber said. “If any of these combinations can be shown to be less toxic and anywhere near as effective as nivolumab plus ipilimumab, ipilimumab plus nivolumab will go the way of the dodo,” he said. “Maybe everyone will use OX40 plus nivolumab. We’ll see if it’s well tolerated; maybe even nivolumab plus OX40 plus ipilimumab.”
If a clinical trial of PD-1/PD-L1 inhibition plus the indoleamine 2,3-dioxygenase inhibitor epacadostat (Incyte Corporation) demonstrates a 50% response rate with median survival in the 35 to 40 month range, Dr. Weber speculated, people will lose interest in combinations with ipilimumab. “But until then, that is the combination to beat.”
Preliminary results of a phase 1/2 study of epacadostat in combination with pembrolizumab, presented at the Society for the Immunotherapy of Cancer annual meeting in November 2015, may be a foreshadowing. In 54 patients with a variety of tumor types, the overall response rate was 53%, with only 2% of patients discontinuing the drug because of treatment-related adverse events.22 Survival results will need another year or two to mature, Dr. Weber said. “This would be kind of nice, but right now the ipilimumab/nivolumab combination is a very effective regimen with long-term survival that’s very impressive.”
Finally, Dr. Weber pointed to the locally injected or intralesional therapies, such as talimogene laherparepvec (T-VEC), PV-10 (Rose Bengal 10% disodium, Provectus), and coxsackievirus A21 (Cavatak, Viralytics). Not only do they generally share the virtue of being devoid of dose-limiting toxicities, but they also may be able to “prime” the immune response, Dr. Weber said, so that “beyond trying to diminish the Treg and MDSC activity, you could augment T-cell activity, causing an influx of them to the tumor and making a cold tumor hot” (Figure 1).
Merrick Ross, MD, Professor of Surgery at MD Anderson Cancer Center in Houston, Texas, has suggested that the programmed cell death induced by the PD-1/PD-L1 agents may not cause the tumor to express antigens in a manner that evokes an immune response.24 On the other hand, viral vectors and a chemoablative agent like PV-10 actually rupture the tumor, releasing and presenting intact antigens. Such an effect, he said, could be synergistic with ipilimumab or other targeted immunotherapies, because it occurs at a different place in the immune system.
The Role of Intralesional Injections
In October 2015, in the midst of the avalanche of checkpoint inhibitor approvals, T-VEC (Imlygic, Amgen), an oncolytic virus therapy derived from herpes simplex virus-1, received FDA approval for the treatment of melanoma lesions in the skin and lymph nodes. T-VEC, injected directly into melanoma lesions, replicates within tumor cells, causing them to rupture. In a multicenter study among 436 patients with unresectable metastatic melanoma, tumor size reductions lasting at least six months occurred in 16.3% of patients versus 2.1% of controls.25
Research into potential mechanisms of action for “bystander” effects—observed reductions in local or distant tumors that have not received intralesional injections—has suggested that antigenic fragments of ruptured tumors may stimulate a tumor-specific improvement in T-cell responses. Research with PV-10,26,27 for example, has indicated that immune responses are tumor specific and associated with increases in CD8+ T cells in both animal and human research. In a phase 2 trial of PV-10 in 80 patients with metastatic melanoma, partial and complete responses were seen in 25% and 26% of patients, respectively, for a best overall response rate of 51%.28 Among patients who had all lesions treated, the best overall response rate was 71% (50% complete responses, 21% partial responses). Uninjected nontarget lesion complete and partial responses occurred in 26% and 7%, respectively. There were no higher-grade treatment-related adverse events. An ongoing phase 3 trial comparing single-agent intralesional PV-10 versus systemic chemotherapy with dacarbazine or temozolomide is assessing treatment of locally advanced cutaneous melanoma. Included subjects are BRAF V600 wild-type and have failed or are not otherwise candidates for at least one immune checkpoint inhibitor. In addition, a phase 1b/2 trial of PV-10 with pembrolizumab in stage IV melanoma patients was initiated in September 2015.
A biomarker analysis from a phase 1b/2 trial of T-VEC plus ipilimumab versus T-VEC alone found increases from baseline after treatment with T-VEC and further after ipilimumab in total and activated CD8+ T cells in peripheral blood, plus increases in CD4 T cells expressing inducible T-cell costimulator. This indicates up-regulated CTLA-4 blockade following ipilimumab treatment. Patients with disease control after T-VEC had 1.4 times as many activated CD8 T cells.29
Although the FDA approval of T-VEC did not support the claim of distant effects, Robert Andtbacka, MD, Associate Professor at the University of Utah School of Medicine, said those effects were clearly evident in his clinical experience and have been reported with the other intralesional therapies. “They all have good effects in the injected lesions, also a regional response, and they also produce, to some extent, distant responses. They are all well tolerated and all potentially have the ability to modify the immune system so that when they are used in combination with other therapies they may improve responses.”
Could an effect on distant disease, the ultimate cause of mortality in melanoma, be among the most important contributions of the intralesional therapies? “Current adjuvant therapies do not work as well as we would like them to,” Dr. Andtbacka said. “So intralesional therapies in a neoadjuvant setting could reduce the risk of recurrence.” In the phase 3 OPTiM trial, he said, the risk of developing new distant metastatic lung, liver, or visceral disease was reduced significantly (59%) among patients receiving T-VEC compared with granulocyte-macrophage colony-stimulating factor (GM-CSF). “This indicates to us that by giving T-VEC in these patients with regional disease, we may potentially reduce the risk of visceral disease.” A multinational, phase 2 neoadjuvant study comparing T-VEC plus surgery to surgery alone is ongoing.30