March 21, 2014

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."

Click to enlarge the illustration.
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."
Click to enlarge the illustration.
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}

Click to enlarge the illustration.
Layer #3: "If pathogens successfully evade the innate response...the adaptive immune 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."
Click to enlarge the illustration.
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)?
Click to enlarge the illustration.
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.

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