April 10, 2014

"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."

Data at ASCO becomes increasingly more anticipated
as Moffitt Cancer Center tells PV-10's immuno-oncology story

If I had to boil my curiosity of Moffitt's clinical work down to one question, it would be what happened to the eight melanoma patients about whom the cancer center presented clinical data at the 2014 annual meeting of the American Association of Cancer Research ("AACR") this past Sunday. Moffitt will provide more data at the 2014 annual meeting of the American Society of Clinical Oncology ("ASCO") in early-June. The patients had metastatic melanoma per the study protocol, and while they should be Stage IV patients, their specific staging (e.g., M1a, b or c) is as yet unknown.

I'd like to thank @bradpalm1, an internist and shareholder, for collaborative thoughts that form some of this blog post's bases.

As a follow-up to my post What PV-10 is doing is “unprecedented” about Moffitt's AACR 2014 poster presentation, here are some additional questions and thoughts. Quoted remarks come from the company's April 7th press release.
a. Why hasn't Moffitt's AACR 2014 poster been released by Provectus
In the past when Moffitt presented PV-10 data, at the 2012 annual meeting of the Society of Surgical Oncology ("SSO") and AACR 2013, the company has made posters available after the conferences end. This approach seems in keeping with conference rules about the timing of disseminating material presented at the conference. AACR 2014 ended on Wednesday, April 9th. Provectus provided comments by Moffitt's Dr. Pilon-Thomas, but no poster. What's the big deal? The big deal [on the poster I guessing and/or what it may imply and one could infer] should be (a) clinical detail of the eight patients and (b) the broadening and deepening of PV-10's overall mechanism of action.

By "embargoing" the poster for a time, presumably after ASCO, Moffitt focuses attention on its clinical work at the Chicago cancer conference and ensures it has greater impact when unveiled in early-June. I'm guessing Moffitt, in addition to presenting a poster at ASCO, may publish the results of their Phase 1 feasibility study in a medical journal.
b. "...clinical data on 8 melanoma patients that demonstrated significant decreases in melanoma cells in injected tumors and uninjected bystander tumors 7-14 days after PV-10 injection as evidenced by pathologic evaluation confirmed with immunohistochemical staining of biopsy specimens for melA (a marker of melanoma)."
Notable: significant decreases in melanoma cells in injected and non-injected tumors, in 7-14 days after injection

In this human feasibility study Moffitt confirmed what they previously found in their murine model work:
"Recently, PV-10 has been used as an IL therapy for malignancies including melanoma. In initial clinical testing, PV-10 therapy induced regression of both uninjected as well as injected melanoma lesions [10]. Intralesional BCG has been associated with patient fatalities due to anaphylactic hypersensitivity reactions that have not been reported with PV-10 [20]–[24]. In mice, it has been shown that repeated injections of high dose BCG by the s.c route led to mortality [25], indicating that PV-10 may be safer than BCG for intralesional therapy. In this study, we verified that IL PV-10 resulted in regression of untreated bystander lesions in breast cancer and melanoma mouse models. In both models, IL PV-10 was associated with enhanced tumor-specific interferon-γ secretion. These results confirm that IL PV-10 can induce a systemic anti-tumor immune response that can mediate the regression of untreated lesions." {Bold emphasis is mine} Source: Moffitt's July 2013 PLoS One paper Intralesional Injection of Rose Bengal Induces a Systemic Tumor-Specific Immune Response in Murine Models of Melanoma and Breast Cancer
And, PV-10 acts rapidly, directly on tumors into which it is injected as well as indirectly (i.e., manifested by the acts of the immune system) on distant non-injected tumors.
c. "The researchers showed that these changes in tumors were accompanied by increased populations of CD3+, CD4+ and CD8+ T cells along with NKT cells in peripheral blood. T cells from one patient were purified and exhibited increased interferon-gamma expression when exposed to the patient's pre-treatment melanoma cells."
Notable: NKT cells in peripheral blood

This is the first time Moffitt has broached the topic of NKT cells, which (together with dendritic cells) are thought of as a bridge between innate and adaptive immunity. @bradpalm1 calls NKT cells the assassins of the immune system. See my blog post PV-10 is not bigger than Mother Nature.

"Natural killer T (NKT) cells are a heterogeneous group of T cells that share properties of both T cells and natural killer (NK) cells." The role of NKT cells in tumor immunity: "NKT cells are a relatively newly recognized member of the immune community, with profound effects on the rest of the immune system despite their small numbers. They are true T cells with a T cell receptor (TCR), but unlike conventional T cells that detect peptide antigens presented by conventional major histocompatibility (MHC) molecules, NKT cells recognize lipid antigens presented by CD1d, a nonclassical MHC molecule. As members of both the innate and adaptive immune systems, they bridge the gap between these, and respond rapidly to set the tone for subsequent immune responses. They fill a unique niche in providing the immune system a cellular arm to recognize lipid antigens. They play both effector and regulatory roles in infectious and autoimmune diseases. Furthermore, subsets of NKT cells can play distinct and sometimes opposing roles. In cancer, type I NKT cells, defined by their invariant TCR using Valpha14Jalpha18 in mice and Valpha24Jalpha18 in humans, are mostly protective, by producing interferon-gamma to activate NK and CD8(+) T cells and by activating dendritic cells to make IL-12. In contrast, type II NKT cells, characterized by more diverse TCRs recognizing lipids presented by CD1d, primarily inhibit tumor immunity. Moreover, type I and type II NKT cells counter-regulate each other, forming a new immunoregulatory axis. Because NKT cells respond rapidly, the balance along this axis can greatly influence other immune responses that follow. Therefore, learning to manipulate the balance along the NKT regulatory axis may be critical to devising successful immunotherapies for cancer." {Bold and underlined emphasis is mine}
d. "These data are exciting and illustrate successful translation of our pre-clinical work in mice to clinical results in melanoma patients. With only 8 patients we've been able to clearly observe statistically significant increases in beneficial T cell populations in peripheral blood."
Notable: successful translation, statistically significant, beneficial T cell populations in peripheral blood

Moffitt confirmed in humans what they previously found in mice, which underscores this notion or concept of successful translational cancer research.
“Translational research can be pictured in the following way,” explains Nobel prizewinner Phillip Sharp, PhD, in an interview with SU2C. “I have a scientific insight. I develop a drug for that scientific insight, or a new therapeutic approach . . . You have to find the cancer patient who would respond to this drug, and you have to deliver it to that cancer patient in a compassionate and reasonable way to see if you can get maximal response.” Source: What Is Translational Research by Cat Vasko
e. "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."
Notable: ironically, no longer contained viable tumor tissue

I wonder if "ironically" refers to management's initial guidance to Moffitt about how PV-10 would work, and what they (Moffitt) would see by way of tumor destruction behavior and other pre-clinical and clinical features of PV-10, all of which they ultimately reproduced, repeated, verified and validated. More importantly, if PV-10 induced increased populations of CD3+, CD4+, CD8+ and NK T cells but no tumor-infiltrating lymphocytes ("TILs") were found in resected injected and non-injected tumors in patients after 7 to 14 days, where did all the T-cells go?

PV-10 is injected into an accessible cancerous lesion or tumor. The drug rapidly ablates the tumor (MOA step #1), which go away. At ECC 2013 management noted "...transient cutaneous loco-regional blistering...consistent with the novel tumor-specific immune mediated mechanism of action of PV-10": a sign [?] of MOA step "#2a:" an immune response at the injected site. Bystander tumors, that is non-injected tumors, go away too: MOA step "#2b:" an immune response at distant sites. MOA step #3, in my reworking of the two-step MOA for PV-10, would be longer-term, tumor specific immunity. It would seem reasonable, through the process of steps #1, 2a and 2b, that T cells are fighting the good fight first at the injected and non-injected lesion sites. After winning the fight, I presume they leave (dissipate from?) these sites. Where do they go? Into the [peripheral] blood (or blood stream) and/or the tumor draining lymph nodes ("TDLNs"), which are lymph nodes downstream from the lesions or tumors? It would seem they first stand up to fight the good fight. Then, second, stand down and hang out in their TDLN barracks or factories (my analogy may be getting thin here), and/or travel around the body over time via the blood stream looking to beat up on cancer [in the distant and not so distant future] of the form or substance they previously beat up in the injected lesion (having learned about what to beat up in the injected tumors' microenvironments).
f. "We are following up both the human data and continuing to design more experiments in mice to better explain the systemic immune effects elicited by PV-10 ablation."
Notable: following up, continuing to design

The study protocol was first put up on ClinicalTrials.gov in December 2012. The per patient treatment and evaluation protocol steps appear to be have a one-month time frame: t = 0 or baseline, 7-14 days after treatment, and 21-28 days after treatment. Were all of a patient's lesions injected and characterized as non-injected, or were only a subset studied? Were there multiple study rounds (e.g., 20% of lesions were studies, and then another 20% and then...), or was only round completed for study purposes? Even though the feasibility study was not a clinical trial with endpoints, was survival monitored and measured in some way? The anticipated study completion date was extended to December 2014. Rather than recruit more patients (subjects upon whom to experiment), which Moffitt also may be doing, is the cancer center observing and monitoring the success or failure (remission) states of the eight patients to see how they're doing (including holistic aspects of treatment a patient's primary oncologist might conduct as a matter of course)?

As for "continuing to design," it would seem Moffitt has further murine model work to do to figure out PV-10's immunological MOA. More immune system components and processes like NKT cells are involved (antibody-dependent cell-mediated cytotoxicity ("ADCC") too?) and the immune response is more robust (read: faster, like 3-5 days and not 7-28 days) than they expected.
g. "Provectus is thrilled to collaborate with the immunology and translational medicine experts Moffitt."
Notable: the immunology and translational medicine experts

In regards to ipilimumab (Yervoy) and its anti-CTLA-4 activity: "The achievement has recently won Allison a raft of awards that M.D. Anderson President Dr. Ron DePinho thinks will culminate in the Nobel Prize. "By creating this brilliant approach that treats the immune system rather than the tumor, Jim Allison opened a completely new avenue for treating cancers that's the most exciting and promising area of cancer research today," DePinho says." It was thought "blocking CTLA-4 stimulates the innate immune system, with subsequent activation of adaptive tumor-specific immunity." It's not clear how robust this really is.

Nevertheless, if one follows DePinho's logic, would Craig, Tim and Eric (and Moffitt, although they neither made the discovery nor translated it into a drug) be candidates for the Nobel at some point, perhaps after drug approval, one or two billion dollars of drug sales, near-100% complete responses (assuming properly and sufficiently injected PV-10) and the passage of time, too?
h. "As more data become available on the 'bystander effect' we've consistently observed in our therapeutic trials, we can better position PV-10 to help the most patients."
Notable: we've consistently observed, most patients

Chemoablation with PV-10,
6th International Symposium
on Melanoma, New York City 2009
PV-10's immune response in humans has been observed since the beginning of the company's clinical trial journey (see a slide from a 2009 Provectus principal investigator presentation at a medical conference using metastatic melanoma Phase 1 trial results). Moffitt's AACR 2014 poster presentation, as a snapshot in time of the sum total of their work to date, adds to the body of pre-clinical and clinical work that underscores PV-10's clinical value proposition (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.

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