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"Results showed that for all subjects, BORR was 51% (26% CR, 25% PR) with the amount of tumor burden accessible to PV-10 injection prognostic for outcome...In subjects where all disease was treated (35% of subjects) BORR further increased to 71% (with 50% achieving CR)."
Emblematic of the compassionate use program, the reported success from the metastatic melanoma Phase 2 study is in line with what management has said, and I previously have written: Put enough water onto the fire, and it goes out. Regularly treat the patient with enough PV-10 -- treat as much or all of the accessible disease (the more antigens that result from the more tumors ablated by PV-10 that are presented to the immune system) -- and, over time, the cancer goes away.
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Moffitt Cancer Center has been exploring PV-10's immunologic signaling.
Until such time as Moffitt comments on and/or publishes this aspect of their findings, the establishment of at least local immunologic activity (if not at least the extrapolation of systemic immunologic activity through this study's results) is very notable.
"Appearance of this potentially immune-mediated effect was strongly predictive of outcome."
Moffitt noted PV-10 engendered a higher quality of tumor-infiltrating lymphocytes ("TILs") in its murine model work (Cancer Watch, Vol 22, 21-23 (2013)). Immune cell infiltrate may be prognostic and a predictor of long-term survival. See, for example, Prognostic and predictive value of the immune infiltrate in cancer (2012) or Tumor-infiltrating immune cells and prognosis: the potential link between conventional cancer therapy and immunity (2011).
In addition, regression or stasis of untreated visceral disease should encourage the further consideration and exploration of PV-10 alone and in combination with other therapies for late-stage diseased patients.
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It would seem management is very confident in their belief they will secure breakthrough therapy designation ("BTD"). As I wrote in my investment letter, Provectus’ discussions with the FDA may be requesting accelerated approval for Stage IIIB and IIIC patients with refractory, locally advanced disease, believing they have sufficiently demonstrated to the Agency PV-10’s ability to safely maintain loco-regional control of MM with minimal intervention and delay, reverse or prevent progression to life-threatening visceral disease, and also seeking BTD for Stage IV patients, where “sped up” discussions with dedicated senior Agency staff via this accelerated pathway could help design trials to show the immediate benefits of PV-10 in combination with approved MM drugs like ipilimumab (Yervoy) and vemurafenib (Zelboraf) for late stage or heavily diseased patients.
Finally: "Melanoma patients and their caregivers experience profound discouragement upon recurrence of the serious skin manifestations of this disease. The investigators on this study describe the effect of PV-10 as ‘rapid, durable response’ but as the photographs have documented, many of the PV-10 treated tumors almost appear to have never been present. PV-10 was only injected intermittently, when tumors were present during the first 16 weeks of the study, in stark contrast to typical clinical studies where treatment is given until either resistance is engendered or patients experience unacceptable toxicity. We are gratified that response to PV-10 was demonstrated consistently across all study centers, with minimal intervention in patients refractory to multiple prior treatments. PV-10’s unique mechanism of action, alone or in combination with existing or emerging therapy, has the potential to shift the paradigm in oncology, where an intermittent intervention can dramatically reduce disease burden and may prod the immune system into preventing or arresting the formation of life threatening metastases."
Let us hope the company-described collaborative interactions of Eric, who undoubtedly approved this press release and its contents for issuance (based very likely on his interactions with the Agency), his regulatory affairs team and the FDA lead to the outcome management is unequivocally signaling.
As Moffitt's Dr. Jeffrey Weber, who may be as cynical and skeptical as they come, said (paraphrasing): "The drug has some serious potential as an immune modulator, and it would be very interesting to combine it with checkpoint inhibitors." Immune modulators can either up-regulate or down-regulate natural immune response as needed, enabling people with cancer to have more normalized immune function without the side effects of unnatural medications. Checkpoint inhibitors include "next generation immunotherapies" like anti-PD-1 and anti-PD-L1 agents.
"...[an] historic breakthrough...[:]" ipi + PD-1. "Prof Eggermont said 24 of his 27 years in the field had been ‘very difficult . . . I couldn’t see the light at the end of the tunnel.’ Most attempts had failed because they had concentrated on the wrong thing: activating cancer-fighting T-cells, rather than breaking down the tumours’ defences. He said: ‘All these attempts ended when they came up against the wall of defence. We needed to break down that wall and open up the tumour to attack, which ipi and the anti-PD1s do in different ways. Now it’s a totally different ball game.’" PV-10's ablation breaks down the tumors' defenses. The resulting antigens presented to T-cells and other immune system components harness the immune system. What I think Dr. Weber and Moffitt ultimately will demonstrate for very heavy tumor burdened or late disease patient is: PV-10 + PD-1 > PV-10 + ipi > PV-10 > PD-1 > ipi.