Treating Cancer

In my September 22, 2013 investment letter entitled Why I'm Long Provectus Biopharmaceuticals, which you can find and/or read in its entirety on the blog's page of the same name (see the right sidebar entitled Pages) I wrote:

PV-10, a novel oncology compound being developed by Knoxville, Tennessee-based Provectus Biopharmaceuticals, Inc. (“Provectus” or the “Company”) (NYSE MKT: PVCT), exemplifies innovation over incrementalism, meaningful over marginal, productized technology over hypothetical, and changing the world over accepting the status quo, with not an insignificant amount of serendipity over contrivance. In sum, these form the quintessential essence of a paradigm shift in the treatment of cancer. 

It seems to me traditional modalities of cancer treatment look like this:

Surgery is the first line of defense when early stage cancer first strikes, while therapies and treatments and repetitions and combinations of them are fall back positions as cancer progresses and recurs towards its later stages.

I contend PV-10 is a paradigm shift in the treatment of cancer because it should play key roles in both ends of the disease spectrum illustrated above:

• For earlier stages of cancer (shift #1a), the far greater majority or supermajority of those afflicted (the "silent masses"), the drug may effectively defeat or control local-regional disease to deny, prevent or forestall its metastatic and visceral spread, and present itself as a viable and far better alternative to surgery.

• For later stages (shift #1b), the current focus of most of the biopharmaceutical industry, PV-10 may, as the tip of the treatment spear, in combination with other therapies, bring the immune system back into an immune surveillance (immunosurveillance) state to conquer heavy tumor burden and visceral disease.

See the blog's PVCT page.

Shift #1a. I think the upcoming pivotal Phase 3 trial for unresectable locally advanced cutaneous melanoma helps further make the case that if you truly effectively treat disease in Stage III (or, of course, earlier or much earlier), it forestalls or prevents it from progressing to Stage IV. I believe this because Provectus' metastatic melanoma Phase 2 trial data appeared to highlight that PV-10 injection lasted, as illustrated by progression-free survival (the time between initial treatment and tumor progression) approximately for the duration of the treatment interval of the drug. If the treatment interval was longer, PFS would be longer as well, until at some point complete response were achieved.

The FDA denied the company breakthrough therapy designation determined on the basis of the paucity of data, which I take simply to mean not enough of the data previously presented -- specifically, the sub-group of patients in the Phase 2 trial who had all of their disease treated (28 patients), which is the patient population of the Phase 3 trial.

In the upcoming Phase 3 trial Provectus will measure PFS as the trial's primary endpoint, utilize RECIST 1.1 to measure it, and inject patients every two weeks until CR or PD is achieved (i.e., the duration of the treatment interval will be until one of the two outcomes is achieved). This protocol, which is what oncologists presumably would use when treating patients, thus would see patients with all of their disease treated by PV-10 potentially never progress.

Shift #1b. This aspect of my presumed assumption of PV-10 as a paradigm shift in the treatment of cancer has yet to unfold. I was struck by an early-September article published by Moffitt staffers who include a key PV-10 researcher (Dr. Shari Pilon-Thomas) entitled Immunotherapy Combined With Chemotherapy for Pancreatic Cancer: A Game Changer?

Of note, the immune system’s involvement in cancer development and progression has sparked much interest in recent years. The model of the cancer-immunity cycle suggests an interplay of immune-suppression and immune-stimulation. In normal individuals, a state of immunosurveillance is in place. However, within the tumor microenvironment, inhibitory signals and immunosuppressive cells are present and tip the scale in favor of immune suppression.

The authors go on to write:

Chen and Mellman have delineated the cancer-immunity cycle, which depicts the immune system’s role in controlling tumor growth in normal individuals. Understanding this cycle provides insight into how tumors can evade it...The idea of the cancer-immunity cycle proposes that, for a cancer immune response to be generated, the net balance between immune stimulation versus immune suppression must be tipped in favor of the former. Studies in various cancers have suggested that tumors evade the immunogenic process mostly by factors that promote immunosuppression.

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See the blog's PV-10, and the Cancer Immunity Cycle page.

As researchers better understand how to treat late stage cancer, specifically and directly fighting tolerance and recurrence, I believe Moffitt has further their understanding of the cancer immunity cycle as it relates to the potential role(s) PV-10 does and could play. We may learn more about this in early-November at the 2014 annual meeting of the Society for the Immunotherapy of Cancer.

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"Intralesional Rose Bengal in patients receiving injection of all existing melanoma"

In the video below, Dr. Agarwala discusses PV-10, and Provectus and Moffitt's ASCO 2014 posters.

I think Dr. Agarwala raises a key point. Many Phase 2 patients in Provectus' PV-10 trial were elderly, and received multiple prior therapies and treatment for melanoma that did not work (a "fairly refractory group of patients"). See below; the median number of prior treatments was 6.

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Despite treating patients who appear to have run out of answers and solutions to treat their melanoma before finally receiving PV-10, and presumably having weakened or compromised immune systems, PV-10 nevertheless generated an objective response rate ("ORR") of 51% and achieved a complete response ("CR") of 26% in injected lesions, as well as a 54% ORR in non-injected lesions and a 23% CR in them. Or, about half of the patients in the trial had their tumors shrink (had a response), and a quarter of patients had their tumors shrink completely (go away). Additionally, more than half of the patients had non-injected tumors shrink (had a response), and about a quarter had their non-injected tumors shrink completely (go away).

"Of the 13 consented patients [in Moffitt's feasibility study], 5 had no previous treatment, 6 received ILI or ipilimumab [sold as Yervoy], and 2 received PD-1 blocking antibody; 6 received two or more prior systemic therapy." ILI refers to isolated limb infusion. Other systemic therapies included vemurafenib (sold as Zelboraf), temozolomide or "TMZ" (an orally administered systemic chemotherapy), and carbotaxol (another systemic chemotherapy).

It would seem Provectus' pivotal Phase 3 trial may prove PV-10 has the potential to be better (much better) than what's available today and on the horizon for patients, both in terms of "new melanoma drugs" (e.g., anti-CTLA-4, BRAF and anti-PD-1 agents) and standards of care (i.e., systemic chemotherapy). In particular, the trial would take patients that have progressed on systemic immunotherapies (i.e., anti-CTLA-4 and anti-PD-1 agents), have not responded to them, or cannot receive them.

PV-10 is not bigger than Mother Nature

PV-10 has a two-step (or dual) mechanism of action. Following injection, step #1, PV-10 rapidly ablates the tumor, destroying the diseased (cancerous) but not healthy tissue.

Rapid tumor ablation then, step #2, recruits dendritic cells (antigen presenting cells) that take up a wide variety (a large number) of antigens by sampling the heterogeneous or diverse microenvironment of the tumors in which PV-10 is injected (the more injected tumors, the wider the variety). These dendritic cells presumably lead to the production of large numbers of high quality T-cells. I write "presumably" (and infer large numbers and high quality) because while Moffitt Cancer Center has shown dendritic cell activation and recruitment in their murine model work, they have not yet publicly stated their determination of the role of PV-10 in T-cell activation.

N.B. This blog post liberally borrows or draws from Wikipedia's immune system page. Illustrations that follow come from The innate and adaptive immune systems by Patrick Fisher, University of San Francisco.

"The immune system protects organisms from infection with layered defenses of increasing specificity."

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Layer #1: Physical barriers like skin prevent pathogens like bacteria and viruses from entering the body. Layer #2: "If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response."

I think in some instances Layer 1 and 2 are thought to be one layer or group, as in the diagram to the right.

"Microorganisms or toxins that successfully enter an organism encounter the cells and mechanisms of the innate immune system. The innate response is usually triggered when microbes are identified by pattern recognition receptors, which recognize components that are conserved among broad groups of microorganisms, or when damaged, injured or stressed cells send out alarm signals, many of which (but not all) are recognized by the same receptors as those that recognize pathogens. Innate immune defenses are non-specific, meaning these systems respond to pathogens in a generic way. This system does not confer long-lasting immunity against a pathogen. The innate immune system is the dominant system of host defense in most organisms."

My takeaways, here, are the innate immune system reacts initially and quickly in a general, non-specific way. First, swiftly, non-specifically.

Interestingly, dendritic cells are a component of the innate immune system. "Dendritic cells serve as a link between the bodily tissues and the innate and adaptive immune systems, as they present antigen to T cells, one of the key cell types of the adaptive immune system."

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My takeaway, here, is dendritic cells are a critical link or bridge between the two layers (innate and adaptive) of the immune system. Dendritic cells.

Recall from Moffitt's AACR 2014 abstract: "Further preclinical translational testing has shown that treatment of murine B16 cells with PV-10 leads to release of HMGB1, a soluble Damage Associated Molecule Pattern (DAMP) that is important for activation of dendritic cells (DCs). In the murine B16 melanoma model, there is a significant increase in the number of DCs infiltrating the tumor-draining lymph nodes after IL injection of PV-10. These findings suggest that PV-10 treatment leads to the release of DC activating factors and DC recruitment." {Emphasis is mine}

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Layer #3: "If pathogens successfully evade the innate response...the adaptive immune system...is activated by the innate response."

"The adaptive immune response is antigen-specific and requires the recognition of specific "non-self" antigens during a process called antigen presentation. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by "memory cells". Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it."

My takeaways, here, are the adaptive immune system reacts secondarily and over time in a specific way (assuming it is not waylaid or deceived by cancer cells), and remembers. Second, specifically, memory, immunity.

T-cells are a component of the adaptive immune system. "T cells recognize a "non-self" target, such as a pathogen, only after antigens (small fragments of the pathogen) have been processed and presented in combination with a "self" receptor called a major histocompatibility complex (MHC) molecule. There are two major subtypes of T cells: the killer T cell and the helper T cell. Killer T cells only recognize antigens coupled to Class I MHC molecules, while helper T cells only recognize antigens coupled to Class II MHC molecules. These two mechanisms of antigen presentation reflect the different roles of the two types of T cell. A third, minor subtype are the γδ T cells that recognize intact antigens that are not bound to MHC receptors."

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Recall from Moffitt's AACR 2014 abstract: "In murine models of breast cancer and melanoma, we have shown that IL injection of PV-10 (10% RB in saline solution) leads to ablation of injected tumors and regression of non-injected bystander tumors. In these models, increased anti-tumor T cell responses were measured, supporting the induction of systemic anti-tumor immunity after tumor ablation with PV-10. In our ongoing phase I clinical trial exploring melanoma regression in patients, IL PV-10 has led to a significant decrease of melA positive melanoma cells in the biopsies of both PV10-injected and non-injected lesions. This regression correlated with increased circulating CD3+T cells (p=0.03) in peripheral blood mononuclear cells (PBMC). T cells purified from PBMC from a melanoma patient produced increased IFN-gamma in response to autologous tumor after treatment with PV-10...Further studies to determine the role of PV-10 on T cell activation are ongoing." {Emphasis is mine}

But, what kind of T-cell, as I asked in my post It's all about the T-cells?

I'd like to thank Dr. Sally Church of the Pharma Strategy Blog for helping me to better understand the contexts of vaccines and checkpoint inhibitors. She plans to write several introductory posts regarding the immune system in the context of the immuno-oncology market on her blog. You may want to (should) visit it to read them.

So, where do cancer vaccines (e.g., Amgen's T-Vec, GSK's Mage-A3, etc.) and checkpoint inhibitors (e.g., BMS' Yervoy [ipilimumab] and nivolumab, Merck's MK-3475)?

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As Dr. Church notes, "...vaccines stimulate the innate system and the PD-1 and PD-L1 antibodies [checkpoint inhibitors] are affecting the adaptive system."

Vaccines and checkpoint inhibitors are different kinds of immunotherapies. "Immunotherapy is a medical term defined as the "treatment of disease by inducing, enhancing, or suppressing an immune response". Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies" (Source: Wikipedia's immunotherapy page).

It seems to me, ideally, you'd like to naturally induce or encourage an immune response, rather than artificially manage, reduce or suppress one. Some response, I'd imagine, is better than no response, but the right response presumably is better than too much of a response or "not the right one." Craig has long espoused PV-10 is not nor is the best approach to treating cancer to be bigger than Mother Nature (but to let her do her job).

PV-10, I think, engages both the innate (dendritic cells) and adaptive (T-cells) components of the immune system; hence, the success patients are seeing. I expect we’ll know a lot more from Moffitt about these aspects of PV-10’s mechanism in the next month (i.e., AACR)  and throughout Q2 (e.g., ASCO, post-Chicago, etc.).

My takeaways [of PV-10], here, are swift, non-specific leading to specific, lasting, immunity.

$PVCT: Adam Feuerstein's Bifurcated Position on Cancer Immunotherapy, in general

From his June 28 Biotech Stock Mailbag. Bold emphasis is mine, as is bold underlined.

"Before I address a specific question about NewLink Genetics (NLNK), I want to lay down a bifurcated position on cancer immunotherapy in general. 

Position No. 1: Until I see convincing evidence of efficacy (successful phase III studies, FDA approvals) I am extremely skeptical of any company taking the "vaccine" approach to targeting cancer cells. I define a cancer vaccine as any therapy made up of tumor cells (autologous or patient specific), antigens or other immune-boosting agents designed to provoke the body's immune system to mount an attack on specific types of cancer cells. 

Who's in this cancer vaccine group? Dendreon (DNDN), of course. Provenge is approved, but it's a fluke and a commercial disappointment. The list of companies with failed cancer vaccines is much longer -- Cell Genesys, Genitope, Favrille, Oncothyreon (ONTY), Antigenics (AGEN), CancerVax, etc. 

Despite a lot of convincing evidence debunking the vaccine approach to cancer immunotherapy, tiny biotech companies push ahead -- NewLink, Galena Biopharma (GALE), Vical (VICL), Northwest Biotherapeutics (NWBO), ImmunoCellular Therapeutics (IMUC). I'm not a believer. I'll be happy to admit my error if/when one of these companies produces boffo clinical data. I just don't see that happening anytime soon. 

Position No. 2: The anti-PD1/PDL1 approach to cancer immunotherapy works. These therapies turn off a cloaking device used by cancer cells to hide from a patient's immune system. One way cancer cells grow is by donning molecular camouflage which tricks the immune system into thinking they're normal, healthy cells. The anti-PD1/PDL1 (and anti-CTLA4) drugs turn off cancer's cloaking device. Without the protective camo, the immune system attacks cancer cells as foreign and deadly. 

I just came back from the ASCO annual meeting where Bristol-Myers Squibb (BMY), Merck (MRK) and Roche (RHHBY) presented a lot of astounding clinical data on their respective anti-PD1/PDL-1 therapies. This is the positive direction in which the cancer immunotherapy field is headed. By comparison, cancer vaccine developers are driving into a dead end. 

Back to NewLink and its pancreatic cancer vaccine known as HyperAcute Pancreaa, or algenpantucel-L. Results from an interim analysis of an ongoing phase III study are expected soon. [The official guidance is mid-year.] 

This interim analysis is fundamentally meaningless. At best, it's another biotech catalyst for biotech traders to trade around. 

The most likely outcome of the interim analysis -- to be conducted after half of the expected number of deaths have occurred -- will be a determination to continue the study with final results ready next year. The bar to stop the study early for efficacy is really high -- estimated at a 45% improvement in overall survival for HyperAcute Pancreas relative to the control arm, according to NewLink. 

Notably, NewLink is not conducting a futility analysis concurrent with the early look at overall survival. A futility analysis determines whether an experimental drug is unlikely to confer a benefit relative to control. 

In other words, NewLink only wants to know if HyperAcute Pancreas works so well that victory can be declared early. The company doesn't want to know -- and will not learn -- if the vaccine has no chance of succeeding. 

Unfortunately, this half-blind approach to clinical trials is standard operating procedure for cancer vaccine developers."

Feuerstein's Position No. 1: "I define a cancer vaccine as any therapy made up of tumor cells (autologous or patient specific), antigens or other immune-boosting agents designed to provoke the body's immune system to mount an attack on specific types of cancer cells." ➟➟➟ Throwing around labels, like a cancer vaccine (or the Holy Grail of cancer, among other labels), very often poorly describes what you are trying to describe because you've used a poor label, you aren't using it "fully properly," or you don't fully understand the label you are using.

Let's start with Provectus' Society for Immunotherapy of Cancer (SITC) poster, where the company concluded the immuno-chemoablative response to PV-10 is tantamount to “in situ vaccination.”

PV-10 is not made up of tumor cells, antigens or other immune-boosting agents. It stimulates the immune system by virtue of the very large quantity of relevant and specific antigens the chemoablative properties of the drug facilitate and thus enable to be expressed. I suppose if we're being intellectually honest, PV-10 could be viewed as an immune-boosting agent, depending on what you mean or intend to mean by "boosting."

I don't think the company calls PV-10 a cancer vaccine, although Moffitt might, but I think they might consider it "vaccine-like" in how it stimulates the immune system.

From Wikipedia: "A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as foreign, destroy it, and "remember" it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters."

The bold emphasis above is mine. PV-10, while not being the agent in the context of the verbiage above, does indeed stimulate the immune system. PV-10's chemoablative properties enable the creation of thousands of "agents" -- the very large quantity of relevant and specific antigens created after PV-10 is administered intralesionally into tumors -- that then are (i) recognized by the immune system as foreign, (ii) are remembered by the immune system, and thus (iii) easily recognized and destroyed by the immune system when they are later encountered.

Words matter. "Provoke" does not fully equal "stimulate."

Feuerstein's Position No. 2: "These therapies turn off a cloaking device used by cancer cells to hide from a patient's immune system." ➟➟➟ Anti-PD-1s/PDL-1s are the next wave of interesting immunotherapy agents, but that is neither the full sum nor the end of the story.

PV-10 triggers immune cell mediation, which is natural, after initial chemoablation occurs.  Again, words matter. "Turn off"/"turn on" are artificial, as in doing something artificial to the immune system (and thus, as Craig would say, to Mother Nature). PV-10 harnesses/employ/stimulates the immune system in a manner that, said colloquially, allows Mother Nature to do what she does best.

$PVCT: $DNDN's "Fight Cancer With Immunotherapy"

Dendreon's "Fight Cancer With Immunotherapy" slide presentation and supporting article are a good read. The summary slide describes well, in a nutshell, the value proposition of immunotherapy.

The full presentation follows (click any and all slides below to enlarge them).