April 18, 2014

“The study shows...the bystander response observed in patients...[is] a bona fide immunological response”

"The studies showed that immunohistochemical staining of biopsy specimens for mel A (an immunohistochemical marker of melanoma viability) demonstrated the complete disappearance of viable melanoma cells in both the injected and bystander tumours."
(PV-10 decreases melanoma cells in tumours, ecancer reporter Janet Fricker)
{Underlined emphasis is mine}

The article from which the above quote comes contributes to the picture of PV-10's systemic properties and benefit, and the very meaningful implications of which, becoming clearer. I briefly noted these under the blog's news tab in "...it’s a bona fide immunological response" (April 17, 2014).

"...the complete disappearance of viable melanoma cells in both the injected and bystander tumours"

In my post "Ironically, the original aim of the trial to assess tumor-infiltrating lymphocytes was thwarted when biopsies of patient tumors collected just 7-14 days after PV-10 injection no longer contained viable tumor tissue" I wrote PV-10's clinical value proposition as (see my September 2013 investment letter Why I'm Long Provectus Biopharmaceuticals):
Oncology compound PV-10 is very safe, is very efficacious locally and systemically, robustly stimulates the immune system locally and systemically, creates systemic anti-tumor immunity, is both a targeted therapy and immunotherapy, works on multiple solid tumor cancers, and could be used anywhere from a pre-neoadjuvant to a combination therapy with other cancer treatments.
Provectus clinical studies to date, particularly the 28-patient subset from the metastatic melanoma ("MM") Phase 2 trial who had all disease treated (i.e., all tumors or lesions were injected with PV-10), clearly have demonstrated the drug's ability to destroy injected tumors through rapid ablation (step #1 of the drug's mechanism of action, or MOA). In other words, locally (or loco-regionally) effective. In my post What PV-10 is doing is “unprecedented” I wrote inject PV-10 and the tumor goes away, and does not come back.

Moffitt Cancer Center's Dr. Jeffrey Weber, M.D., Ph.D., a medical oncologist, said patients who die of melanoma die of distant metastatic disease, not locoregional, cutaneous, dermal or soft tissue disease. Well, if you can establish loco-regional control -- PV-10 does this by mostly destroying tumors, rather than just shrinking them -- you have a very good chance of preventing metastatic disease, which should mean you have a very good chance of preventing people from subsequently dying of distant metastatic disease. There is tremendous value in this: local (loco-regional) efficacy.

The MM Phase 2, 28-patient subset used for Provectus' breakthrough therapy designation ("BTD") application, all disease treated, achieved a 71% objective response or OR (complete response, or CR, plus partial response, or PR) and an 82% loco-regional disease control (CR + PR plus stable disease, or SD). 50% (CR) + 21% (PR) and 50% (CR) + 21% (PR) + 11% (SD), respectively. The poster from where this data is taken is hereEffective (true) loco-regional disease control can forestall or prevent metastatic disease.

What has been less established, by virtue a not complete understanding of PV-10's MOA, more questions, great astonishment, and certainly lots of skepticism, is the drug's affect on non-injected lesions (so-called bystander lesions distant or removed from injected lesion sites). These distant non-injected sites can range from bad to worse to evil (i.e., visceral disease). The relevance and importance of PV-10's bystander effect frames and establishes the drug's systemic properties and benefit. Because an injected lesion rapidly ablates -- is destroyed -- the goal of a physician treating a melanoma patient (or any other patient with a solid tumor cancer) would be to inject as many lesions as the oncologist can find and inject. Win as many battles as you can.

But cancer is, to most, viewed as a systemic disease. The evil of cancer is not in what we can see or find or image, but in what we cannot see or find. How do we win the war? How do we kill (cure) cancer wherever it lies in the human body.

Truly demonstrating the bystander effect is one of several ways to establish PV-10's systemic properties, benefits and chops. For example, the MM Phase 2 trial, bystanders untreated, achieved a 54% OR and an 85% loco-regional disease control. 23% (CR) + 31% (PR) and 23% (CR) + 31% (PR) + 31% (SD), respectively. 

The bystander effect is real. Another way one can show this is by the work of a third party like Moffitt, which can reproduce, repeat and validate Provectus' work. In Moffitt's Phase 1 feasibility study, injected and non-injected lesions of an initial group of 8 patients completely disappeared. Thus, Moffitt confirms PV-10's rapid ablative effect and the effective immunological activity of the drug.

"Studies are now underway in an additional seven patients to take biopsies and blood samples at more frequent time intervals after PV-10 injection to elucidate the pathways more clearly."

Since Moffitt unexpectedly missed the window of where the activated T-cells attacked and destroyed both injected and non-injected tumor (which in itself is unexpected given Moffitt's great experience with adoptive cell transfer technology and trials) they’re now taking more frequent blood sampling of these seven additional Stage IV patients as well as more frequent core needle biopsies of areas in question.

Moffitt changed the trial protocol of its feasibility on January 9, 2014 according to ClinicalTrials.gov, and began enrolling the next seven patients later in the month. It is now mid-April. The cancer center should have had sufficient time to process and view tissue samples as well as get blood results of the second group of feasibility study patients.

This information unquestionably should be part of Moffitt's poster presentation and its poster highlights session at the 2014 annual meeting of the American Society of Clinical Oncology ("ASCO").

“The study shows that there are plausible immunological processes that explain the bystander response observed in patients. This isn’t a spurious event, it’s a bona fide immunological response”

Eric's quote, in my view, foretells Moffitt's ASCO 2014 poster. Moffitt should know the results of the additional seven patients. I have to believe Provectus management does as well. Explaining the bystander response is critical to the steps #2a and 2b of PV-10's MOA. Step #2a is the destruction of non-injected lesions. Step #2b is the provision of immunity to the patients thereafter. Spurious, in a medical context, means "simulating a symptom or condition without being pathologically or morphologically genuine."  A bona fide immunological response means that lesions or tumors inaccessible to injection can be shrunk or more likely destroyed (assuming not too heavy tumor burden in the patient) with PV-10.

For most patients whose disease has not progressed to a metastatic stage, winning the war with PV-10 may appear to be in sight. This would be accomplished because PV-10 harnesses the immune system to do what it, the immune system, was intended to do, and kill cancer where we cannot access or see it (i.e., microscopic traces or non-visceral disease). The drug of course must first gain approval, and thus management must manage the regulatory approval process and path.

But what about the war for patients with metastatic disease, and visceral disease. Recall Eric's quote from the company's June 2013 white paper PV-10 Moves Forward by W. Alexander, which discussed Moffitt's translational research work: "“What we learn from leveraging the clinical data with these new nonclinical results highlights the crucial role translational medicine can play in clinical development,” observed Dr. Wachter in an interview. While more frequent dosing could potentially improve outcomes, for patients with extensive tumor burden inaccessible to PV-10 injections a combination therapy strategy may be attractive, he said."

The article went on to frame management's belief of the robustness of PV-10's immunological activity for visceral disease (i.e., in melanoma, Dr. Weber's Stage IV M1c patients): "PV-10 murine research demonstrated unambiguously, Dr. Wachter noted, that tumor burden is a critical variable in predicting response to a combination therapy. It has been suggested that earlier research into therapeutic melanoma vaccines faltered because tumor burden grew beyond the immune system’s capacity for control before the vaccine could develop its full effect. “We think that the combination of PV-10 with something like a kinase-inhibitor has the potential to dial back or reduce tumor burden even better than an anti-CTLA-4 agent while the systemic PV-10 immunologic effect is developing. The kinase inhibitor would do the early work against visceral disease until PV-10 can catch up and take the baton across the finish line.”"

The story behind PV-10's immunological activity has yet to fully unfold. Winning the war on cancer means helping all stages of cancer patients defeat their affliction.

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