"Together, these studies support the induction of increased tumor-specific immunity after co-inhibitory blockade in combination with IL PV-10 therapy."

Moffitt Cancer Center's PV-10-related abstract from the 29th annual meeting of the Society for Immunotherapy of Cancer ("SITC") was made available today by SITC's Journal for ImmunoTherapy of Cancer. The company issued a press release and filed an associated 8-K, and the stock also was halted because of Moffitt and the abstract.

Efficacy of intralesional injection with PV-10 in combination with co-inhibitory blockade in a murine model of melanoma

PV-10 is a 10% solution of Rose Bengal that is currently being examined as a novel cancer therapeutic. We have previously shown that intralesional (IL) injection of PV-10 into a single subcutaneous B16 melanoma tumor led to regression of both the injected tumor and uninjected B16 lung lesions. Tumor regression correlated with the induction of systemic anti-melanoma T cell immunity. In melanoma patients, IL injection of PV-10 has led to regression of treated lesions as well as untreated bystander lesions. In this study, we have examined whether IL PV-10 and co-inhibitory blockade could improve anti-tumor immunity and regression of melanoma. B16 cells were injected into C57BL/6 mice to establish one subcutaneous tumor. Treatment of this lesion with a single IL injection of PV-10 alone led to partial regression of the injected B16 lesion. Systemic administration of anti-CTLA-4 or anti-PD1 antibodies in combination with IL PV-10 resulted in increased tumor regression and improved survival in this model. Treatment with PV-10 also led to the induction of T cells that produced IFN-γ (495 ± 198 pg/ml) in response to B16 cells but not to irrelevant MC-38 cells. Combination therapy with IL PV-10 and anti-CTLA-4 led to increased IFN-γ responses to B16 (1235 ± 191 pg/ml, p < 0.05). In another experiment simulating heavy tumor burden using a bilateral model, systemic administration of anti-PD-L1 antibodies in combination with IL PV-10 led to regression of the injected B16 lesion as well as a bystander subcutaneous lesion on the opposite flank (p < 0.01 compared to mice treated with anti-PD-L1 antibodies or IL PV-10 alone). Together, these studies support the induction of increased tumor-specific immunity after co-inhibitory blockade in combination with IL PV-10 therapy.

It strikes me there are two general takeaways:

1. PV-10 works with everything, and
2. Provectus' drug should expand the relevance and use of co-inhibitory blockade agents (i.e., PD-L1s, PD-1s, and CTLA-4s) from (a) late-stage cancer in the U.S. to (b) Stage III and IV disease globally.

In the context of Moffitt's abstract, and the underlying work from which it was drawn and written, PV-10 works with [at a minimum] co-inhibitory blockade agent categories PD-L1, PD-1 and CTLA-4. Reference material on this should be:

• PV-10's so-called orthogonality with other drugs (i.e., the likely minimal risk of PV-10 causing clinically relevant drug-drug interactions is likely minimal). See the paper In vitro inhibition of human liver cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes by rose bengal: system-dependent effects on inhibitory potential and Provectus' associated press release, and

• Provectus' combination therapy patent application with Pfizer (filed in 2012), Combination of Local and Systemic Immunomodulative Therapies for Enhanced Treatment of Cancer, of which Pfizer shares in economics only related to PV-10 & CTLA-4 combinations. The application's claims should cover combinations of PV-10 and {PD-L1s, PD-1s, CTLA-4s, and other drug categories}.

In the context of global and stage-related relevancy and use, challenges of approved and investigational co-inhibitory blockade agents include non-specificity, dose limiting toxicity, and cost:

• PD-L1, PD-1 and CTLA-4 cancer immunotherapies are non-specific immunotherapies that do not achieve sufficient, let alone notable, levels of complete responses,

• Their toxicity and side effects limit the amounts of them that can be given to patients. Side effects have to be, when possible, physician-managed, and

• Their prohibitive cost to research and make, and thus price to sell, very likely will limit their use in the U.S., where the duration of use to achieve longer survival, ultimately ineffective as it is, would be more than $1 million per patient. Their cost/price should largely diminish or prohibit their use elsewhere in the world: "We've kind of maxed out what we're either willing or able to pay for these kinds of drugs, so it's a problem when you start combining them. It can't just keep going exponentially, so that eventually it will be $1 million a year to get treated -- that's crazy." (a quote from Moffitt's Dr. Jeffrey Weber, M.D., Ph.D., Reuters' New cancer therapy comes of age, cost a 'toxic' side effect, September 2014)

Presumably, combining with PV-10 would make these drugs more relevant and increase their use because:

• An effective, long-lasting, sustainable immune response for late-stage patients (where all disease burden is not accessible to PV-10 injection) requires both their use and PV-10's: non-specific and specific immunotherapies, respectively. The human body has specific and non-specific immune system components: the innate and adaptive immune systems, respectively. See my blog post entitled PV-10 is not bigger than Mother Nature, 

• Less of them would be used, potentially reducing or mitigating their dose limiting toxicities and side effects, and

• The duration of their use then should be shorter were their combination with PV-10 to be more effective, reducing overall treatment cost. 

Returning to the detail of the abstract, specific takeaways include:

• Moffitt touching on three keys to cancer treatment using PV-10 and a co-inhibitory blockade agent: (i) tumor regression, (ii) improved survival, and (iii) impact (tumor regression) on both treated and untreated lesions:

• Systemic administration of anti-CTLA-4 or anti-PD1 antibodies in combination with IL PV-10 resulted in increased tumor regression and improved survival in this model.
• In another experiment simulating heavy tumor burden using a bilateral model, systemic administration of anti-PD-L1 antibodies in combination with IL PV-10 led to regression of the injected B16 lesion as well as a bystander subcutaneous lesion on the opposite flank (p < 0.01 compared to mice treated with anti-PD-L1 antibodies or IL PV-10 alone).

• Specificity works, by saying they achieved T-cell responses to B16 cells and not MC 38 cells. The study was focused on melanoma (i.e., B16 cells). MC 38 cells relate to or reference colon cancer.
• Treatment with PV-10 also led to the induction of T cells that produced IFN-γ (495 ± 198 pg/ml) in response to B16 cells but not to irrelevant MC-38 cells.

• Moffitt's previous pre-clinical work, published in 2013, Intralesional Injection with PV-10 Induces a Systemic Anti-tumor Immune Response in Murine Models of Breast Cancer and Melanoma (AACR 2013 poster, PLoS One paper), noted PV-10's ability to destroy tumors (i.e., complete responses). This work, and PV-10's ability to destroy tumors (i.e., complete response), was followed up in the cancer center's human feasibility study (ASCO 2014). The study design underlying their SITC 2014 revelations required Moffitt to wound -- and not destroy -- the tumors. In order to demonstrate the ability of PV-10 in combination with a co-inhibitory blockade agent to achieve tumor regression, improve survival, and impact both treated and untreated lesions, Moffitt had to inject tumors with a sub-optimal amount of PV-10 (i.e., "wound") so as not to achieve a complete response, and be able to show combinations could impact the tumor.

• Reading the abstract, it struck me that Moffitt ordered the effectiveness of the co-inhibitory blockade agent in combination with PV-10 as, first, the PD-L1, and tied for second, the PD-1 and CTLA-4. Given that, which do you think of Big Pharma is more worried (as a non-combo partner, or non-owner of the PV-10 lead in the combo)?

Click to enlarge.