provectus IS a t-cell company

H/t InvestorVillage poster bradpalm1: A research team from the University of Illinois at Chicago (UIC) published a paper in July entitled The Potential of Intralesional Rose Bengal to Stimulate T-Cell Mediated Anti-Tumor Responses (Maker et al., J Clin Cell Immunol 2015, 6:4). This same team previously published results of their murine model work and research on PV-10 for colon cancer. See June 5, 2015 blog post Intralesional Injection of Rose Bengal Induces an Anti-tumor Immune Response and Potent Tumor Regressions in a Murine Model of Colon Cancer.

Blog post takeaways:

• Rose Bengal (PV-10)/PV-10 (Rose Bengal) induces/generates/creates/leads to anti-tumor immunity. To some the so-called Holy Grail of cancer therapy is achieving durable [system- or body-wide] anti-tumor immunity in a cancer patient.

• PV-10 can prime the immune system (through the direction injection of the compound into cancerous lesions), and help it defeat distant cancerous lesions around the body.

• The compound exposes antigens to the immune system that otherwise would not be exposed, or that otherwise would escape detection by (and thus presentation to) the immune system.

• PV-10 can help with T cell generation & circulation, even after treatment with immune checkpoint inhibitors fails.

• UIC's work reproduced Moffitt Cancer Center's (Moffitt's) work, which reproduced Provectus' founders' work.

• UIC's work that contributed to their paper was funded in part by a grant (non-specific to Provectus and PV-10) from the National Institutes of Health.

Recall that Provectus has a two-prong approach to fighting (killing) cancer: (i) local effect/tumor ablation (anti-tumor cytotoxicity) and (ii) systemic effect/tumor-specific immune response (induction of anti-tumor immunity)

Click to enlarge. Image source

UIC and Moffitt independently reproduced the veracity of both prongs:

Click to enlarge. Image source

UIC's paper reviews PV-10's agnosticity in destroying tumors into which it is injected (i.e., anti-tumor cytotoxicity):

• Melanoma,
• Breast cancer,
• Ovarian cancer,
• Gastric cancer, and
• Sarcoma.

The paper discusses PV-10's agnosticity in generating anti-tumor immunity resulting from local tumor injection (i.e., from resultant anti-tumor cytotoxicity):

• Melanoma,
• Breast cancer, and
• Hepatocellular carcinoma (HCC).

The UIC team appears to have conducted murine model work on PV-10 in HCC, noting "Our current research is establishing the role of RB in generating anti-tumor immune responses in gastrointestinal cancer and liver metastases:"

"Furthermore, in syngeneic orthotopic models of murine hepatocellular carcinoma (HCC), RB similarly induced chemoablation in all treated tumors. Twenty-one to 81 days after RB treatment, when re-challenged with the same tumor, durable immunity was demonstrated in 14/14 animals without measurable tumor formation, whereas B16-F10 melanoma tumors, i.e., non-HCC cells, were able to be established in 13/13 animals [20]. Additionally, immunity to establishment of a new HCC tumor could be created through adoptive transfer of splenocytes from treated animals. This was an interesting finding given that analysis of splenic composition from animals with B16 melanoma that experienced distant lung tumor regression after RB treatment of flank tumors did not demonstrate any difference in the percent of T cells, Tregs, NK cells, B cells, myeloid derived suppressor cells, or macrophages [15]. The authors further demonstrated that bystander lesions disappeared or decreased in size in HCC models, whereas, no bystander tumors were ever observed to resolve in nude mice without a competent T-cell immune system. These experiments established that, similar to melanoma, in immunocompetent mice with orthotopic primary hepatocellular carcinoma flank tumors, an anti-tumor response can be induced by priming the animals with RB treatment of tumors. These experiments raise the possibility that RB induced cytotoxicity exposes antigens and mounts an immune response that may protects animals from additional tumor formation that can be adoptively transferred to other animals using splenocytes." {Underlined and bolded emphasis is mine}

Speaking of antigens, it's all about the antigens:

"These experiments established that in human and murine melanoma and breast cancer, there appeared to be an antigen-driven T-cell response that has the potential to activate T-cells and impart antitumor responses in bystander lesions and distant metastases."

Why are antigens important? Because they facilitate the priming of the immune system through their presentation to it:

"These findings may imply that tumor response in the primary lesion may be able to prime the immune system of patients for activity against distant lesions."

The UIC team's conclusions could be profound, among them:

• "RB-mediated tumor cell death may expose tumor antigens that may otherwise evade immune detection."

• "Though most profoundly described in melanoma cells, clearly an immunoreactive malignancy, the effect has been shown to be not limited to one specific type of malignancy. 

• "Decrease in tumor burden and stimulation of an immune response with PV-10 has been demonstrated in animal models of metastasis, and correlations of these responses in clinical studies is consistent with such results." Provectus' CTO Dr. Eric Wachter, PhD has said in a 2013 white paper: "PV-10 murine research demonstrated unambiguously, Dr. Wachter noted, that tumor burden is a critical variable in predicting response to a combination therapy." See Radiation (September 22, 2015) on the blog's Current News page.

• "That PV-10 treatment can potentially increase circulating cytotoxic T-cells, even in patients who were previously treated with immune-activating checkpoint blockade, supports the possibility that RB induced cytotoxicity may activate T-cells that are responsible for the bystander effect on untreated lesions."

• As such, intralesional therapy with RB may be a promising new mode of therapy to stimulate T-cell mediated anti-tumor immune responses."

UIC's work was conducted in part under an NIH grant.

Safely specific (a.k.a a diseased tissue-specific way of generating a systemic response)

An August 2014 Drug Discovery Today article entitled Loco-regional cancer drug therapy: present approaches and rapidly reversible hydrophobization (RRH) summarized the shortcoming of systemic chemotherapy:

"Insufficient drug uptake by solid tumors remains the major problem for systemic chemotherapy. Many studies have demonstrated anticancer drug effects to be dose-dependent, although dose-escalation studies have resulted in limited survival benefit with increased systemic toxicities."

A similar criticism -- that is, the cost-benefit of systemic toxicity and greater survival -- could be made of checkpoint inhibitors (e.g., anti-CTLA-4s, anti-PD-1s, anti-PD-L1s), although there presumably is greater drug intake of these immunotherapies than chemotherapies.

Craig has long said (paraphrasing) one of the keys to solving the problem of cancer -- to generating correct, sustainable and thus successful systemic responses -- was to solve the problem of specificity. Other contributors to this proper response included route of delivery, and how the therapeutic or therapy in question induced cells to die. Specificity, manner of cell death, and route of delivery all importantly contribute to the safety, robustness and durability of a therapeutic or therapy's correct and successful systemic response.

The Drug Discovery Today article above continues:

"One solution to this has been the idea of loco-regional drug treatments, which offer dramatically higher drug concentrations in tumor tissues while minimizing systemic toxicity." {Underlined emphasis is mine}

Once they knew rose bengal (PV-10) had the necessary kind of specificity (and thus solved this problem) -- destroying only diseased tissue while leaving healthy tissue untouched or unaffected -- Craig contends they knew the main problem mostly was solved.

Other agents induce autophagy (where cells eat themselves). Can those agents induce this action only in cancerous cells, and not normal ones too?

Other agents can be delivered intralesionally or intratumorally, with the goal of delivering more drug product into the tumor. Without specificity, however, would not both the tumor and its surrounding normal tissue be affected, leaving a confused immune system to try and sort out what it must and must not do?

Craig believed a loco-regional agent could generate the correct systemic response, but needed a diseased tissue-specific way of doing so to make it practically effective and sufficiently safe: PV-10 (rose bengal).

$PVCT: Immunology Data on PV-10 to Be Presented at the #AACR Annual Meeting

In today's PR, Craig said: "The researchers at Moffitt are providing valuable insights into how PV-10 harnesses the immune system in specific response to the injected tumor. Although the study being presented was done in murine models of melanoma and breast cancer, the currently open clinical trial at Moffitt is designed to investigate this mechanism in melanoma patients. We are pleased to enhance our understanding of intralesional PV-10 and its potential to produce a systemic benefit in cancer patients."

$PVCT: Simplifying Things

In designing PV-10, Craig's philosophy was and is to allow immune system to do the job mother nature intended it to do.

In addition to its robust safety, the drug has 3 unique characteristics that deeply matter to PV-10's proposition and make it so broadly efficacious:

1. Delivery mechanism: Intra-tumoral injection,
2. Multiple targeting: A full expression of antigens in context, and
3. Tissue specificity: Destruction only of diseased tissue

Some context: PV-10's immunologic mechanism of action lies in a separate category than, say, Provenge. Provectus' drug triggers an internal vaccination (internal antigenization), while Provenge operates on the basis of an external vaccination (with very marginal efficacy).

Late-night $PVCT...

“A further impetus toward teasing out the precise mechanism of how PV-10 can exert a systemic 
immune response in patients,” said Dr. Sarnaik in an interview, “is to allow us to rationally combine PV-10 treatment with some of the exciting emerging immunotherapies for metastatic melanoma.” The focus at Moffitt, Dr. Sarnaik continued, is on discerning the presence of immune cell infiltrate in untreated tumors after PV-10 injections into other lesions. “We are really interested in harnessing immune cell infiltrate as a form of treatment,” he said, noting also that while creating cancer vaccines has been thought of traditionally as one of the Holy Grails of cancer research, cancer vaccines have turned out to be not strong enough to generate an adequate immune response. CANCER WATCH, VOL. 22, FEBRUARY 2013

I kept coming back to this portion of the article for two reasons. First, was Sarnaik's quote rationally combining PV-10 with other exciting emerging immunotherapies. What, PV-10 isn't exciting? Second, was his quote about harnessing immune cell infiltrate as a form of treatment. A better cancer vaccine because of PV-10?

The crux of the matter is that PV-10, as a local agent, needs to show systemic potential for life science investors, Big Pharma and the FDA to view the drug as clinically relevant. This is the local agent "burden of proof." There must be systemic potential to be relevant for treating cancer after surgery, where cancer is viewed by definition as a systemic disease. PV-10 is an drug with tremendous local efficacy and before unseen systemic benefit (even more so than systemic agents).

But PV-10 still is a local agent.

The mindset of the industry -- medical oncologists and hematologist-oncologists, but not surgeons -- is that a local agent has to be combined with a systemic agent to be relevant.  The industry does not yet realize how much of an impact PV-10 will be just as a local agent. All it can currently understand is that PV-10 works, and harnesses the immune system in novel manner. It is obvious to industry PV-10 will get even better systemic results when combined with other agents, or, other agents will get better results when combined with PV-10.

I am getting hung up about trying to understanding PV-10's potential as a monotherapy, but that's not where the industry's mindset currently resides (i.e., as I wrote above, it's in combination for now). That should come, however, and probably quickly.

A tumor's core is an anaerobic necrotic area where more dangerous cancer cells reside, compared to the outer layers and exterior of the tumor where cancerous cells are less abnormal and virulent. Standard chemotherapy or radiation kills the "easy" cancerous targets on the periphery of the tumor. The "hard" targets in the anaerobic core are difficult for drugs and radiation to destroy. A very Darwinian natural selection process occurs. The more hardy and vicious variants in the core survive, feeding off of and expanding into the room provided by the destruction of the easier-to-kill cancer cells at the periphery. Tumors re-occur and the next generation of them is drug- and radiation-resistant, having selected for the more virulent population. If you miss with the first round, everything is made worse for the patient.

The historic and current work on cancer vaccines faces the challenge of not being strong enough to generate an adequate immune response. Like with failed chemotherapy or radiation, where the treatment miss makes everything worse for the patient, vaccines are inducing tolerance by repeated exposure to antigens, convincing the immune not to react to tumor-associated antigens.

Recall Craig et al.'s conclusion at SITC:

PV-10 in situ vaccination. Let the the antigen presenting cells (APCs) pick the antigen, rather than the other way around (as others are doing) and kill the tumor in situ. Let the APCs do their job and present antigens to T cells.

Moffitt, however, through their focus on adoptive T cell immunotherapy, believes PV-10 induces better T cells. T cell activation to very specific tumor targets. The ability to transfer immunity. Notice Moffitt's AACR abstract about PV-10 inducing a systemic anti-tumor immune response in murine models of melanoma and, now, breast cancer. More cancer indications validated by Moffitt on the way?

Moffitt, it seems to me, thinks PV-10 is the pathway to a more potent (i.e., generates a much stronger immune response), more effective (i.e., it heals, it cures), more broad (i.e., multi-indication) cancer vaccine.

I admit this post is a work in progress. The much greater point is understanding what PV-10 does to the immune system. PV-10: The Holy Grail? The cure for cancer? Perhaps...

$PVCT: It's the #immune system, #stupid.

"It's the economy, stupid" is a slight variation of the phrase "The economy, stupid" which James Carville had coined as a campaign strategist of Bill Clinton's successful 1992 presidential campaign against sitting president George H. W. Bush. (Source: Wikipedia).

To understand PV-10 is to understand the relationship between chemoablation and immune-mediated signaling. It's what Craig means when he says the immune system responds in direct proportion to the degree of insult. Think of PV-10 chemoablation as the proxy for the degree of insult, which is rapid, complete and durable in the case of PV-10. Moffitt should say the same thing in its conference presentation(s) and contemporaneous peer-reviewed publication.

A good amount of work -- creative, innovative, pragmatic, historical, scientific, medical literature-based, etc. -- went and a continues to go into dosing, of historical and upcoming clinical trials, of certain indications, of pre-clinical work on newer indications.

Yes, management doesn't talk openly about dosing, nor do they talk openly about several other topics of import and value.

The thing that makes you go hmmmm... Rose Bengal has an established safety history, a short half-life in the bloodstream, and is excreted via the liver and kidneys. The half-life is measured in minutes, like 15-30 or thereabouts. The drug is gone from the body almost immediately, so there is never enough of it to kill remote (untreated) tumors like what injected (treated) tumors receive via intratumoral delivery. PV-10 is long gone before the immune system removes the untreated ones. Hmmmm...