It's all about the T-cells

I'm looking forward to reading Moffitt Cancer Center's American Association for Cancer Research ("AACR") annual meeting abstract next month, viewing the associated poster in April, and learning about what if anything they present at the American Society of Clinical Oncology ("ASCO") annual meeting in May/June. I presume they'll present something at ASCO because of Sondak's already scheduled PV-10 presentation at the 4th European Post-Chicago Melanoma/Skin Cancer Meeting. See Moffitt @ ASCO 2014? (February 10, 2014) under the blog's News tab.

There are three topics of their possible work I hope their poster presentation at AACR and any potential presentation(s) at ASCO would elucidate:

1. PV-10's "mechanism of immune response," or the mechanism by which the drug induces systemic immunity (I think PV-10's primary mechanism of action, rapid tumor ablation following injection, is understood),
2. Improved responses (i.e., tumor destruction and/or shrinkage) from combining PV-10 and other immunotherapies,
3. PV-10's role and responsibility with respect to adoptive cell therapy ("ACT").

Let's re-visit the Discussion section of Moffitt's July 2013 PLoS paper Intralesional Injection of Rose Bengal Induces a Systemic Tumor-Specific Immune Response in Murine Models of Melanoma and Breast Cancer.

Click on the figure to enlarge it: Discussion, portion 1

Click on the figure to enlarge it: Discussion, portion 2

While Provectus pursues the initial local path to approval for PV-10 of locally advanced cutaneous melanoma, Moffitt is more interested in PV-10's systemic properties and benefit, and more than likely its application to patients with metastatic melanoma and other late-stage solid tumor cancer indications. Some observations of the above, which was first presented at AACR 2013 and discussed more in the paper:

- First, in murine model work, Moffitt confirmed PV-10 generated an anti-tumor immune response that shrunk or destroyed untreated tumors (red underlined portions 1, 2 and 3 in paragraphs 1 and 2). They observed the systemic potential of PV-10 for both breast cancer and melanoma.

- Second, they hypothesized that large amounts of tumor debris created by the rapid ablation that followed PV-10's injection into tumors, debris containing antigens (thus, large amounts of debris should mean large numbers of antigens), are taken up by dendritic cells ("DCs") (red underlined portion 4 in paragraph 3). DCs, antigen-presenting cells, present (display) antigens they've taken up to the body's immune system's T-cells.

- Third, Moffitt suggested combining PV-10 with other immunotherapies may lead to better results in patients with metastatic melanoma (red underlined portion 5 in paragraph 4).

- Finally, fourth, they demonstrated immunity could be transferred from mice with PV-10 treated tumors to mice with untreated tumors, hypothesizing (I think) that more and better T-cells could be created using PV-10 (better ones) together with ACT (more of these better ones) to then use on more than one patient (red underlined portions 5 and 6 in paragraph 4).

There are T-cells, and then there are T-cells. There are different types of T-cells, each with a distinct function: helper, cytotoxic, memory, regulatory, natural killer, and mucosal associated invariant. "Cytotoxic T cells ("CTLs") destroy virally infected cells and tumor cells." "Regulatory T cells, formerly known as suppressor T cells, are crucial for the maintenance of immunological tolerance." "Natural killer T cells ("NKT cells")...are also able to recognize and eliminate some tumor cells and cells infected with herpes viruses."

CTLA-4 and PD-1 cell receptors are the so-called brakes of the immune system, limiting its response. Taking the brakes off by inhibiting these blockade receptors (with anti-CTLA-4/PD-1 agents) allows for a more active and vigilant immune system. CTLA-4 and PD-1 agents, I think, help out with or activate these regulatory T-cells.

PV-10, on the other hand, I think, helps out with or activates CTLs, by virtue of the drug's rapid ablation causing tumor debris containing antigens to be taken up by DCs that then display them to this type of T-cell. "For long it has been discussed whether ablated tumor debris is able to induce a systemic immune response."

So, while activating regulatory T-cells and CTLs (cytotoxic T-cells) both may result in tumor destruction and shrinkage, regulatory T-cell activation by checkpoint inhibitors is not permanent and eventually resisted or overcome, whereas CTL activation by PV-10 may result in [permanent?] immunity.

"CTLs specific for tumor antigens play a major role in the immunity against cancer." Will Moffitt show PV-10 specifically activates these CTLs?

If the checkpoint inhibitors remove the brakes of the immune system, allowing it to shrink tumors but not activate the specific T-cells responsible for destroying tumor cells, the utility of combining them with PV-10 would be to have these inhibitors reduce tumor burden and thus the "weight" on the immune system, thereby allowing it to be better stimulated by PV-10. Such combination use would be very helpful for late stage metastatic melanoma patients where tumor burden is high.

Moffitt has conducted trial work on both MK-3475 (Merck) and nivolumab (Bristol-Myers) PD-1 agents. Will Moffitt present combination work with PV-10 involving one of these agents?

"Adoptive T cell therapy involves the isolation and ex vivo expansion of tumor specific T cells to achieve greater number of T cells than what could be obtained by vaccination alone.  The tumor specific T cells are then infused into patients with cancer in an attempt to give their immune system the ability to overwhelm remaining tumor via T cells which can attack and kill cancer.  There are many forms of adoptive T cell therapy being used for cancer treatment; culturing tumor infiltrating lymphocytes or TIL, isolating and expanding one particular T cell or clone, and even using T cells that have been engineered to potently recognize and attack tumors" (Source: Tumor Vaccine Group, UW Medicine). The current approaches for ACT seem to focus on ex vivo (out of the tumor/body) improvements to T-cells; that is, endeavoring to make more of them better external to the patient.

But, as Moffitt first introduced in the February Cancer Watch article, per Dr. Sarnaik, PV-10 appears to improve the quality of T lymphocytes (cytotoxic?). It does this in vivo (in the tumor/body), of course. Perhaps Moffitt's novel approach is to utilize T-cells taken directly from the patient’s blood after they have received a PV-10 injection, which primes the tumor antigen specific T-cells first. Then, with active immunization already established by PV-10, they expand the number of those T-cells in the lab to greater numbers for therapeutic infusion, and thus even greater response success.

March (abstract), April (presentation), May (abstract(s)?), June (presentation(s)?)...

Waiting for the FDA... (updated)

Earlier today Provectus issued an 8-K regarding the company's ongoing interaction with the FDA following the December 16th meeting with the Agency: "Reference is made to...a Type C meeting with the FDA Division of Oncology Products 2 on December 16, 2013 to discuss the Company’s oncology drug, PV-10. Subsequently, the Company took the opportunity to provide input into the documentation of meeting minute notes. It is the opinion of the Company that this may have delayed the process of receiving the final meeting minute notes. Therefore, the Company will communicate further guidance from the FDA once the meeting minute notes have been received, which is expected shortly. It is also the Company's opinion that the delay has no bearing on the FDA's decision regarding the efficacy of PV-10 but is rather a matter of observing governmental processes. This delay also has no bearing on the Company's discussions and negotiations with parties outside the FDA's jurisdiction."

I don't think there is any bad news here. There is, however, no official good news, yet. For now, maybe just this message: "The final meeting minutes didn't arrive within a reasonable period of time following the close of trading on January 15th (you know, the date by which we promised to get back to you) for us to confirm our planned PR before issuing it." Management gave itself no wiggle room by including a capitalized byline in its December 18th press release Provectus Type C Meeting With FDA Oncology Division Held December 16, 2013: OFFICIAL MINUTES EXPECTED BY JANUARY 15, 2014. The FDA set a performance goal (government fiscal year 2008-2012) of returning minutes within 30 days of a meeting 90% of the time (see here, a link found by/courtesy of a shareholder and blog reader). From the prior link, as of September 30, 2008, the Agency was not achieving performance goals for meeting management, providing minutes within 30 days 61% of the time. Even though meeting management performance may have improved since then, it's not unreasonable to still expect potential delays. Based on Provectus' 8-K today, this appears to be the case.

My investment thesis remains the same.

Bullish as the December 18th PR likely was intended to be by the inclusion of the January 15th date, I believe management's intent (temporarily unsuccessful by virtue of delay) was to have wanted to simply communicate what clearly has to be groundbreaking recognition by the FDA that local therapy PV-10 can treat systemic disease. Once PV-10 presumably had been acknowledged as a viable and needed treatment for cancer (melanoma), an important ideological decision for the Agency to embrace and make, I would imagine the FDA and Provectus subsequently worked together on outlining agreements, disagreements, issues for further discussion, and action items (coming out of the December 16th meeting) to pave a mutually acceptable approval pathway for the drug. For example, recognizing local agent PV-10 can treat cancer, a systemic disease, undoubtedly would require more relevant and appropriate endpoints. To arrive at agreement, it's quite possible the time taken between the December 16th meeting and now would have comprised, among other things, collaboration between the parties on data and statistical analysis in support of the right endpoint(s). Based on my reading of readily available administrative and correspondence documents of previously approved drugs (and the interactions of their sponsors and the FDA), all of this would be documented in some form or fashion in final meeting minutes. I'm sure such documentation, and its receipt by Provectus, would be necessary for this management to feel comfortable issuing a milestone press release.

Until then, we patiently wait some more.

Updated (1/15/14): As I noted above, I previously read about actual experiences and interactions of sponsors (whose drugs ultimately were approved) with the FDA in the kind of meeting Provectus had with the Agency on December 16th. In them, the FDA and sponsor reached a consensus during the meeting. The sponsor subsequently waited until the Agency had codified the consensus reached (i.e., memorialized and sent final meeting minutes) before the sponsor communicated the outcome to the public. Provectus appears to be in the same situation.

Provectus presumably reached a consensus with the FDA on December 16th, and clearly is waiting to receive codification of the consensus from the Agency (i.e., return of the final meeting minutes) before issuing a press release describing it. I believe this consensus will provide clarity for PV-10's approval pathway. I further believe the pathway may either be a one- or two-step process, both providing discernible timelines from the drug's commercialization.

It seems to me the company is discussing an accelerated path to market for PV-10 with the FDA when recalling the changes management recently made to Provectus' website presentation (see Paying Attention (January 15, 2014) under the blog's News tab).

Click to enlarge the figure.

Regardless, we await management to speak substantively about clarity and this potentially groundbreaking outcome. I remain very bullish about Provectus' prospects.