Revolutionize, Perfect, Quintessential

In regards to PV-10, Moffitt Cancer has said over the last couple of years:

• Single Injection May Revolutionize Melanoma Treatment, Moffitt Study Shows (Moffitt press release, August 2013),

• PV-10 might offer the perfect way to prime the immune system (interview of Moffitt's Dr. Jeffrey Weber, MD, PhD, ASCO 2014, May-June 2014), and

• [PV-10 injection]...stimulated release of interferon-gamma, the “quintessential antitumor cytokine.” (interview of Moffitt's Dr. Amod Sarnaik, Dermatology Times, May 2015).

Speaking of cytokines...

Image and article source

Cytokines are the messengers of the immune system. Cytokines are substances, either proteins or glycoproteins, secreted by immune cells. They have autocrine and paracrine functions, so that they function locally or at a distance to enhance or suppress immunity. In cancer therapy, we generally use cytokines to enhance immunity. 

Cytokines regulate the innate immune system: natural killer (NK) cells, macrophages, and neutrophils. They also regulate the adaptive immune system, the T and B cell immune responses. In the immune system, cytokines function in cascades. Thus clinical trials of individual cytokines are rarely useful, since cytokines tend not to work individually. Some of the individual cytokines that have been tested and found ineffective for cancer treatment include interleukin 1 beta (IL-1 beta), although it may be useful because it helps to mediate the severe toxicity of interleukin 2 (IL-2). Tumor necrosis factor (TNF) certainly sounded promising, but in fact caused severe hypotension when used systemically. Interleukin 4 (IL-4) showed minimal anti-cancer activity and was toxic. Interleukin 6 (IL-6) had some activity against cancer cells, but turned out to be a growth factor for myeloma cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF), used primarily in stem cell transplant to reconstitute the myeloid series, has been studied for melanoma with controversial results. 

Which cytokines are important for cancer? IL-2 and interferon-alfa 2b are two cytokines approved by the FDA for treatment of cancer. IL-2 has demonstrated activity against renal cell, melanoma, lymphoma, and leukemia. Interferon has activity in the same histologies but also in Kaposi's sarcoma, chronic myelogenous leukemia, and hairy cell leukemia. Overall, cytokines are substances that appear to have application in the treatment of hematologic malignancies or immunogenic tumors. {Underlined emphasis is mine}

Dr. Weber

An interview of Moffitt Cancer Center's Dr. Jeffrey Weber, M.D., Ph.D. by OncLive's Andrew Roth, Expert Discusses Integration of PD-1 Inhibitors Into Clinical Practice, was published last week. I found several of Weber's answers to Roth's questions separately notable by themselves and germane to PV-10 (when viewed in the context of his involvement with the drug).

Dr. Weber's public positions on intralesional therapies and PV-10 are interesting, as has been his work with Provectus' drug when one considers his other clinical work. I have not been able to find disclosure statements for him that included Provectus—if you find any, let me know. Into November 2014 sample Weber disclosures included:

Click to enlarge. ESMO 2014-related (i.e., September)

Click to enlarge. November 6, 2014

Moffitt and Dr. Weber's work with PD-1s pembrolizumab and nivolumab are:

• Moffitt Cancer Center Plays Pivotal Role in FDA Approval of New Anti-PD-1 Inhibitor Keytruda for Metastatic Melanoma (Moffitt press release, September 2014): "Jeffrey S. Weber, M.D., Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence at Moffitt Cancer Center, was one of the lead investigators of the PD-1 clinical trial which led to the drug receiving breakthrough status from the FDA. “Pembrolizumab is the first PD-1 drug to be approved by the FDA, and it is a clearly effective drug that will prolong survival for many patients with metastatic melanoma.  This approval is a real advance, and a major milestone in the treatment of the disease,” Weber said."

• Bristol-Myers Squibb Receives Accelerated Approval of Opdivo (nivolumab) from the U.S. Food and Drug Administration (Bristol-Myers press release, December 2014): "“The approval of Opdivo gives patients and physicians an important new treatment option for a population where they were once very limited,” said Jeffrey S. Weber, MD, Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center. “For the first time, a PD-1 blocking antibody has shown a response rate of 32% in a Phase 3 randomized clinical trial of patients with unresectable or metastatic melanoma, who have progressed following first line therapy.”"

Click to enlarge. Source link

Moffitt and Dr. Weber also have been involved in three other melanoma approvals, ipilimumab, vemurafenib, and the combination of dabrafenib and trametinib:

• (2011) "Researchers at several NCI-designated cancer centers were lead investigators in the pivotal phase III clinical trial that ultimately led to FDA approval in March 2011of ipilimumab as a treatment for advanced melanoma. These researchers included Dr. F. Stephen Hodi Exit Disclaimer of the Dana-Farber/Harvard Cancer Center, Dr. Jeffrey A. Sosman Exit Disclaimer of the Vanderbilt-Ingram Cancer Center, Dr. Jedd D. Wolchok Exit Disclaimer of the Memorial Sloan-Kettering Cancer Center, and Dr. Jeffrey S. Weber Exit Disclaimer of the Moffitt Cancer Center and Research Institute."

• FDA Approves Personalized Medicine Drug For Melanoma (Moffitt press release, August 2011): From Moffitt's website, "Jeffrey S. Weber, M.D., Ph.D., and others at Moffitt contributed significantly to the approval and testing of the melanoma drug Vemurafenib, including important laboratory work in developing an inhibitor to overcome resistance to the drug that has led to improved outcomes."

• Moffitt Cancer Center Instrumental in FDA Approval of Revolutionary Two-Drug Combo to Treat Advanced Melanoma (Moffitt press release, January 2014): "“Melanoma is the most aggressive type of skin cancer and the leading cause of death from skin disease,” said Jeffrey S. Weber, M.D., Ph.D., director of Moffitt’s Melanoma Research Center of Excellence. “This new combination therapy is a huge step in the right direction for the treatment of melanoma, and our researchers played a large role in bringing this treatment option to patients.”"

Of seven drugs the FDA has approved for melanoma since 2011, according to Moffitt and Dr. Weber, they have been instrumental or significantly participated in six approvals.

To date Dr. Weber has publicly associated himself (so to speak) with PV-10 two times, both around ASCO 2014 (June).

• He was senior author of Moffitt's ASCO abstract and poster entitled Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions, which discussed some of the cancer center's clinical work. Moffitt's Dr. Amod Sarnaik, M.D., however, stood next to the poster and presumably spoke about it during relevant sessions, and

• Immediately following ASCO, Weber said "PV-10 might offer the perfect way to prime the immune system."

To add context to the above, however, he:

• Does not believe intralesional ("IL") therapies have a singular role in treating late-stage melanoma with heavy tumor burden and spread of the disease to visceral organs. See Debating Systemic Intralesional Therapies (April 16, 2014) on the blog's Archived News I, and

• Also described Amgen's IL agent tamilogene laherparepvec ("T-Vec") as (November 2014) "...a niche drug that would be best used to prime the immune system and follow up with a drug such as pembrolizumab, nivolumab, ipilimumab, or a combination of those."

In the moment, as it relates to Provectus' upcoming pivotal Phase 3 trial for locally cutaneous advanced melanoma, the company has an initial pathway to licensure. When they finally start their trial, management finally would have advanced their drug candidate to the final clinical stage prior to approval (pending of course a positive outcome for the trial). A "fully FDA-approved" and fully operational Phase 3 protocol should be tantamount to a prospective drug label; that is, who to treat and how to treat them.

Returning to Dr. Weber's OncLive interview:

OncLive interview, Figure 1

Takeaway: He notes three approved drugs (ipi, pembro and nivo), and the IL agent (T-Vec) that has begun testing in combination with ipi and will be combined with pembro. Anti-CTLA-4 and PD-1 drugs do not sufficiently work singularly for late-stage patients. Combinations now are the order of the day for this patient population where drug permutations would be graded based on a combination of safety ("keep toxicity down") and efficacy ("boost the response rate). Combining two checkpoint inhibitors, or drugs that release the brakes of the immune system, does not make sense (you're further releasing the brake?) from safety, efficacy and cost perspectives. Combining a stimulatory agent (starting the engine) with an inhibitory one (i.e., a checkpoint blockade agent) makes more sense in order to garner a better grade.

OncLive interview, Figure 2

Takeaway: The role of chemotherapy is being diminished and presumably eventually eliminated as drugs are approved for different melanoma patient populations as safer and more effective alternatives to chemo. He notes three approved immunotherapies (ipi, pembro and nivo). IL-2, also an immunotherapy, was approved in 1998. If and when T-Vec is approved (for metastatic melanoma), it would be an alternative for certain patients. If and when PV-10 is approved (for locally advanced cutaneous melanoma), it would be an option for another segment of melanoma patients.

OncLive interview, Figure 3

Takeaway: I found this answer interesting because Provectus principal investigator and St. Luke's University Health Network medical oncologist Dr. Sanjiv Agarwala said at ECC 2013, "[d]iscussing the interest in the use of PV-10 by his surgical colleagues, Dr. Agarwala added other potential benefits of pre-surgical intralesional injection—turning unresectable lesions into resectable ones and stimulating the immune system to lower the odds of recurrence." Neoadjuvant therapy refers to treatment given prior to the primary one (i.e., in this context, surgery—turn an unresectable lesion into a resectable one so it may be removed with surgery or excision). PV-10 achieved a 71% objective response and 50% complete response in the subgroup of 28 patients from Provectus' melanoma Phase 2 trial who received PV-10 into all existing melanoma lesions (i.e., no un-injected lesions).

OncLive interview, Figure 4

Takeaway: I don't believe Moffitt has commented on progress it may have made in determining a biomarker for PV-10. At this year's J.P. Morgan Health Care Conference, Roche's Chief Financial Officer Dr. Alan Hippe, Ph.D. said 70% of the company's projects in development have a biomarker hypothesis, which underscores Roche's deal with Foundation Medicine. Provectus's upcoming pivotal Phase 3 trial would include patients with "indolent, low-burden, low bulk with normal LDH."

Should Dr. Weber lend his voice—appropriately and in context—to the process of approving PV-10, his could be an important one to the FDA, and one that could help frame the drug's initial and potential eventual roles in treating advanced melanoma in particular and melanoma in general.

"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.

More of Better > More or Less of Worse

In a February 2013 Cancer Watch article entitled Back to Phase 1: Understanding Systemic Effects of PV-10, Moffitt Cancer Center's Dr. Amod Sarnaik, M.D. said of the cancer center's Phase 1 feasibility study, result of which later were presented at AACR 2014 and ASCO 2014:

“A further impetus toward teasing out the precise mechanism of how PV-10 can exert a systemic immune response in patients 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... 

...“We generate large numbers of T-lymphocytes, but we don’t have control over their quality. We think one of the limitations is that the T cells you get out of the tumor just aren’t good enough.” PV-10, however, does cause an immune response, suggesting that a combination treatment may improve the quality of the T-lymphocytes and have a greater impact on the disease... {Underlined emphasis is mine}

A potent, long-lived systemic immune response to solid tumor cancers should:

(i) Originate at the tumor sites themselves, 

(ii) Require a broader array of tumor antigens to be released and presented, 

(iii) Require this array to be comprised of pristine, un- or non-denatured antigens (i.e., whole tumor antigens, not antigen fragments,), and 

(iv) Result from the subsequent, more comprehensive, T-cell response.

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MD Anderson Cancer Center surgical oncologist and Provectus principal investigator Dr. Merrick Ross, M.D., noted in a recent video, below, while speaking at the setting of ASCO 2014:

"The rapid lysis of the tumor and when the tumor is lysed it does not denature the antigen. So the antigens are expressed in a way where an inflammatory response can occur and therefore antigen presentation probably is up-regulated and enhanced, which could lead to a systemic host response." {My transcription, and underlined emphasis is mine}

The idea is to present as many un-denatured or pristine antigens as possible to dendritic cells ("DCs") and antigen presenting cells ("APCs"). Showing fewer pristine antigens or more denatured ones cannot generate a sustainable, systemic, specific, anti-tumor response. Showing more pristine ones should have the opposite and a much better effect.

Said another way, by a shareholder, blog reader and internist whose patients include those afflicted with cancer:

"Rapid lysosomal-mediated tumor lysis following IL injection of PV-10 uniquely produces pristine, un-denatured antigens that up-regulates antigen presentation to DCs and APCs with a resultant systemic immune response (to paraphrase Merrick Ross). The fidelity of these un-denatured tumor antigens (akin to injecting whole tumor antigens, not antigen fragments, into a patient) is what provokes a very accurate and specific immunological T-cell response that bystander tumors are vulnerable to (presuming they don’t possess too many mutated antigens due to selection pressure from previously therapies)." {My transcription, and underlined emphasis is mine}

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Roche's Genentech's Drs. Daniel Chen, M.D, Ph.D. and Ira Mellman, Ph.D.'s Oncology Meets Immunology: The Cancer-Immunity Cycle provides the opportunity to illustrate the interplay between (a) immune checkpoint blockade [Step #7] and (b) the creation, release and presentation of antigens [Steps #1 and 2], and the subsequent priming and activation of the immune system [Step #3]. I write interplay of these steps because they appear to be what industry thus far is focusing on when it considers combination therapies for late stage diseases, and permutations of treatments and therapeutics from each of these steps in an eventual combination.

The illustration below builds on (is revised by me of) Chen & Mellman's Figure 1:

The generation of immunity to cancer is a cyclic process that can be self propagating, leading to an accumulation of immune-stimulatory factors that in principle should amplify and broaden T cell responses. The cycle is also characterized by inhibitory factors that lead to immune regulatory feedback mechanisms, which can halt the development or limit the immunity. This cycle can be divided into seven major steps, starting with the release of antigens from the cancer cell and ending with the killing of cancer cells. Each step is described above, with the primary cell types involved and the anatomic location of the activity listed. Abbreviations are as follows: APCs, antigen presenting cells; CTLs, cytotoxic T lymphocytes.

Click to enlarge.

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Various types of treatments and/or therapeutics in Steps #1, #2 and #3 may create and release antigens ("Antigen Release"), present them to DCs and APCs ("Antigen Presentation"), and prime the body's T-cells ("T-Cell Priming).

See Chen & Mellman's section entitled Initiating Anticancer Immunity: Antigen Release.

Attempts to activate or introduce cancer antigen-specific T cells, as well as stimulate the proliferation of these cells over the last 20 years, have led to mostly no, minimal or modest appreciable anticancer immune responses. The majority of these efforts involved the use of therapeutic vaccines because vaccines can be easy to deploy and have historically represented an approach that has brought enormous medical benefit (reviewed by Palucka and Banchereau, 2013). Yet, cancer vaccines were limited on two accounts. First, until recently, there was a general lack of understanding of how to immunize human patients to achieve potent cytotoxic T cell responses. This limitation reflects continued uncertainties concerning the identities of antigens to use, their mode of delivery, the types of adjuvants required, and the proximal characteristics of the desired T cell response (Palucka and Banchereau, 2013). Second, the presence of the immunostat in the tumor microenvironment may dampen or disable antitumor immune responses before clinically relevant tumor kill can occur. Thus, as long as these negative signals are in place, the prospects for vaccine-based approaches used alone are likely to be limited. {Underlined emphasis is mine}

Therapeutic vaccination is not the only approach to accelerating and expanding the production of T cell immunity. Because anticancer T cells can be produced spontaneously, there is a growing appreciation that the tumor itself represents a type of endogenous vaccine. Accessing the naturally occurring source of cancer-associated antigens avoids problems associated with selection and delivery (Heo et al., 2013, van den Boorn and Hartmann, 2013). This approach is also convenient, but achieving it requires detailed knowledge around whether standard of care chemotherapy or targeted therapies are compatible with immunotherapies. Some therapies are thought to cause tumor cell death in a fashion that promotes immunity (reviewed in Zitvogel et al., 2013). However, it is unclear whether this effect can be accurately predicted and will, in any event, require empirical study. Chemotherapy, radiation therapy, and targeted therapies must also be evaluated for their effects on the immune system. Although it is assumed that many might be antagonistic, there are some reports that others might promote T cell activity (Demaria et al., 2005, Duraiswamy et al., 2013, Hiniker et al., 2012, Ott et al., 2013, Postow et al., 2012, Stagg et al., 2011, Zitvogel et al., 2013). {Underlined emphasis is mine}

See Chen & Mellman's section entitled Presentation, and T Cell Priming.

Another exciting development is that the initial demonstrations that genetically modified autologous T cells could be reinfused into patients to yield substantial clinical benefit, at least in certain B cell malignancies (Grupp et al., 2013; reviewed in Kalos and June, 2013). The most well developed of these is the use of “CARs,” or chimeric antigen receptors, in which a patient’s T cells are transfected with a construct encoding an antibody against a tumor surface antigen (typically CD19) fused to T cell signaling domains (Kochenderfer and Rosenberg, 2013). Similar approaches are under investigation with recombinant T cell receptors (reviewed in Kalos and June, 2013). The procedure avoids the need for immunization and may even overcome mechanisms of immune suppression by overwhelming the system through infusion of large quantities of the modified T cells. This can force the revolution of the Cancer-Immunity Cycle, enhancing the accumulation of stimulatory immune factors, and potentially promotes eventual self-propagation of the cycle. The potential limitations here, which are yet to be fully determined, include whether the approach can be extended to cancers beyond hematologic malignancies, whether the delivery of large numbers of monospecific T cells will cause resistance due to antigenic drift, and whether the toxicity issues already identified can be safely managed. {Underlined emphasis is mine}

See Chen & Mellman's section entitled T Cell Priming and Activation.

Whether tumor antigens are delivered exogenously or are captured and presented by DCs endogenously, another strategy for intervening in the Cancer-Immunity Cycle involves the control of T cell activation. This is the presumed primary mechanism of action of anti-CTLA4 antibodies, such as ipilimumab, which blocks the interaction of the major negative regulator of T cells (CTLA4) with its ligands B7.1 and B7.2 (CD80 and CD86; Qureshi et al., 2011). Thus, during antigen presentation in lymphoid organs (or in the periphery), the expansion of T cell responses is disinhibited, thereby promoting the production of autoreactive T cells, including tumor-specific T cells. The lack of selectivity in T cell expansion combined with the fundamental importance of CTLA4 as a checkpoint may underlie the significant immune-related toxicities seen in patients treated with ipilimumab (Hodi et al., 2010). {Underlined emphasis is mine}

This second illustration below builds on (is revised by me of) Chen & Mellman's Figure 2:

The numerous factors that come into play in the Cancer-Immunity Cycle provide a wide range of potential therapeutic targets. This figure highlights examples of some of the therapies currently under preclinical or clinical evaluation. Key highlights include that vaccines can primarily promote cycle step 2, anti-CTLA4 can primarily promote cycle step 3, and anti-PD-L1 or anti-PD-1 antibodies can primarily promote cycle step 7. Although not developed as immunotherapies, chemotherapy, radiation therapy, and targeted therapies can primarily promote cycle step 1, and inhibitors of VEGF can potentially promote T cell infiltration into tumors—cycle step 5. Abbreviations are as follows: GM-CSF, granulocyte macrophage colony-stimulating factor; CARs, chimeric antigen receptors. {Underlined emphasis is mine}

Click to enlarge.

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In the cancer immunity cycle, where certain drugs (based on known and yet to be known factors, notably stimulatory and inhibitory) promote a step (or potentially more than one step), who owns what "real estate" (i.e., who owns what drugs) should be key to understanding the competitive landscape, and where it eventually leads. As the researchers, industry and the FDA combine therapies to address the still unmet needs of late-stage cancer patients, ownership of cancer assets used in whatever combinations may and do work (and thus eventually are approved) translates into sales, profit and return on investment (in R&D).

Step #1: Chemotherapies and radiation therapies likely produce more antigen fragments than whole antigens, but antigens nevertheless. Chemotherapies are commoditized (read: inexpensive, not so profitable, and growing obsolete). Radiation therapy is owned and delivered by physicians. There are numerous targeted therapies owned by various pharmaceutical companies. They may or may not generate whole and/or fragmented antigens, but it seems their owners are worried about the dismantlement of their franchises, as some rush to combine and partner with PD-1 and PD-L1 agents.

Step #2: These agents presumably facilitate the presentation of the antigens released in Step #1, and include failed (or as yet ineffectively utilized) vaccines, CD40 agent owners (like Genentech-Roche, among others), and not-so-valuable-properties-because-of-widespread-use (read: un-patentable, like INF alpha).

Step #3: There potentially is more real estate here. Already owned includes, notably, Bristol-Myers' approved CTLA-4 agent (ipilimumab), and CD137, OX40 and CD27 agents by Pfizer and Roche, among others.

Step #7: The PD-1 owners include Bristol-Myers (Opdivo) and Merck (Keytruda). The PD-L1 owners include Roche and AstraZeneca. IDO owners include, among others, Incyte (non-exclusive combination study relationships/agreements with AstraZeneca, Bristol-Myers, Merck, and Roche) and NewLink (exclusive, now, to Roche)

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Celgene's expansion of its license relationship with Sutro today (building on 2012's initial arrangement), provides Celgene with real estate, and potentially special ones at that. In terms of real estate, while the Big Biotech can access CTLA4, PD-1 and PD-L1 via Sutro, it notably also gets LAG-3 and TIM-3 (the next generation of immune checkpoint inhibitors?).

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The illustration below builds on (is revised by me of) Chen & Mellman's Figure 3 (note LAG-3 and TIM-3 inhibitors, alongside PD-1 and PD-L-1):

Each step of the Cancer-Immunity Cycle requires the coordination of numerous factors, both stimulatory and inhibitory in nature. Stimulatory factors shown in green promote immunity, whereas inhibitors shown in red help keep the process in check and reduce immune activity and/or prevent autoimmunity. Immune checkpoint proteins, such as CTLA4, can inhibit the development of an active immune response by acting primarily at the level of T cell development and proliferation (step 3). We distinguish these from immune rheostat (“immunostat”) factors, such as PD-L1, can have an inhibitory function that primarily acts to modulate active immune responses in the tumor bed (step 7). Examples of such factors and the primary steps at which they can act are shown. Abbreviations are as follows: IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; CDN, cyclic dinucleotide; ATP, adenosine triphosphate; HMGB1, high-mobility group protein B1; TLR, Toll-like receptor; HVEM, herpes virus entry mediator; GITR, glucocorticoid-induced TNFR family-related gene; CTLA4, cytotoxic T-lympocyte antigen-4; PD-L1, programmed death-ligand 1; CXCL/CCL, chemokine motif ligands; LFA1, lymphocyte function-associated antigen-1; ICAM1, intracellular adhesion molecule 1; VEGF, vascular endothelial growth factor; IDO, indoleamine 2,3-dioxygenase; TGF, transforming growth factor; BTLA, B- and T-lymphocyte attenuator; VISTA, V-domain Ig suppressor of T cell activation; LAG-3, lymphocyte-activation gene 3 protein; MIC, MHC class I polypeptide-related sequence protein; TIM-3, T cell immunoglobulin domain and mucin domain-3. Although not illustrated, it is important to note that intratumoral T regulatory cells, macrophages, and myeloid-derived suppressor cells are key sources of many of these inhibitory factors.

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Additionally, according to FierceBiotech, the real estate is special:

"Sutro's team believes it has devised a much better way to build ADCs--those precise cancer cell-killing constructs made up of a targeting antibody, linker and payload--and bispecifics, teeing up potentially best-in-class products that promise to be more efficiently and consistently manufactured. Using biochemical synthesis, they've hatched a technology that can bypass the current approach to biologics by genetically engineering drugs that are much simpler to make, more akin to small molecules." {Underlined and bold emphasis is mine}

PV-10's effectiveness is attributed to its physical chemistry and small molecule nature.

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Moffitt presents pre-clinical (murine model) data about PV-10 in combination with co-inhibitory blockade at SITC 2014 (Provectus' press release on the topic is here). Chen and Mellman note "inhibitors shown in red [in their Figure 3] help keep the process in check and reduce immune activity and/or prevent autoimmunity distinguish between checkpoint," but distinguish between CTLA-4, and PD-1 and PD-L-1:

"Immune checkpoint proteins, such as CTLA4, can inhibit the development of an active immune response by acting primarily at the level of T cell development and proliferation (step 3). We distinguish these from immune rheostat (“immunostat”) factors, such as PD-L1, can have an inhibitory function that primarily acts to modulate active immune responses in the tumor bed (step 7). "

The presentation could explain Moffitt's Dr. Jeff Weber, M.D., Ph.D.'s contention PV-10 may be the perfect immune system primer. What does being the perfect primer mean, and entail?

Provectus recently revised its Fact Sheet to note more work by Moffitt, this time on biomarkers:

What happened to the next cohort of the Phase 1 feasibility study? Of the total enrollment of 15 patients, 8 were reported on at AACR/ASCO 2014. April 2014 article PV-10 decreases melanoma cells in tumours, which followed AACR 2014, noted:

Studies are now underway in an additional seven patients to take biopsies and blood samples at more frequent time intervals after PV-10 injection to elucidate the pathways more clearly.

Moffitt's presentation could discuss whether or not PV-10 promotes steps #4, #5 and/or #6 of the cancer immunity cycle. If so, why and how?

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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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Moffitt

H. Lee Moffitt Cancer Center & Research Institute has issued strongly worded press releases related to recent pre-clinical and clinical cancer trial work and research successes.

Single Injection May Revolutionize Melanoma Treatment, Moffitt Study Shows

August 22, 2013, Tampa, Fla. – A new study at Moffitt Cancer Center could offer hope to people with melanoma, the deadliest form of skin cancer. Researchers are investigating whether an injectable known as PV-10 can shrink tumors and reduce the spread of cancer. PV-10 is a solution developed from Rose Bengal, a water-soluble dye commonly used to stain damaged cells in the eye. Early clinical trials show PV-10 can boost immune response in melanoma tumors, as well as the blood stream.

Moffitt Cancer Center Instrumental in FDA Approval of Revolutionary Two-Drug Combo to Treat Advanced Melanoma

January 23, 2014, Tampa, Fla. – Moffitt Cancer Center researchers have laid the groundwork for a revolutionary new combination therapy for the treatment of advanced melanoma – melanoma that cannot be removed surgically or has spread to other areas of the body. The newly FDA-approved therapy, Mekinist (trametinib) in combination with Tafinlar (dabrafenib), is one of the biggest advancements in melanoma treatment in the past 30 years.

Moffitt Cancer Center Plays Pivotal Role in FDA Approval of New Anti-PD-1 Inhibitor Keytruda for Metastatic Melanoma

September 4, 2014, Tampa Fla. – The U.S. Food and Drug Administration (FDA) announced the approval of a new cancer immunotherapy today to treat patients with metastatic melanoma, Keytruda (pembrolizumab) by Merck & Co.

Quotes and statements from Moffitt about PV-10

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Immune Surveillance

Following up on my Juxtaposition blog post, there is the potential for a melanoma combination therapy Phase 1 (or 1b)/2 trial of PV-10 and a checkpoint inhibitor, which management briefly discussed on their 2Q14 conference call.

Eric: As Pete mentioned earlier, we're also looking beyond single-agent therapy with PV-10 to address the needs of patients with more extensive disease, particularly those with visceral tumors that are not injectable. One attractive and complementary approach may be to combine PV-10 with a systemic immunotherapy, such as an immune checkpoint protein inhibitor. Immune checkpoint protein inhibitors, such as anti-CTLA4, anti-PD-1, and anti-PD-L1 agents, are an important advance in the treatment of melanoma and other cancers, another subject of intense development in our industry. 

However, while these drugs represent an important step forward, like any drug they are not perfect and they might be improved. As was clearly presented by the medical oncology community earlier this summer at ASCO, using an agent like PV-10 to prime the immune system could be synergistic in combination with such a systemic agent. 

Our patent application on this strategy was published in 2012 and we've been vigorous by pursuing this approach since. The nonclinical research we first presented at the Society for Immunotherapy of Cancer Annual Meeting in 2012, together with ongoing translational clinical research on PV-10's mechanism of action that we were sponsoring at Moffitt Cancer Center and our own Phase 2 data, provide a rationale for combination testing of PV-10. 

This development track, separate from the Phase 3 study I discussed earlier, could represent a path forward for patients with significant disease burden not amenable to intralesional injection, and is a possible candidate for co-development with one or more pharmaceutical or biotech companies. {Underlined emphasis is mine}

Eric wouldn't insert statements about this topic into his comments until and unless at least minimally substantive progress has been made towards this end. He first addressed a combination study via St. Luke’s Cancer Center and Temple University's and principal investigator Dr. Sanjiv Agarwala, M.D.'s presentation at the 10th European Association of Dermato-Oncology (EADO) congress in May ("Commencement of combination studies in Stage IV disease in second half of 2014"). The reality of a combination study/trial probably is dependent on the partnering pharmaceutical company's, the one with the checkpoint protein inhibitor to be combined with PV-10, interest in and willingness to:

• At a minimum, run and shoulder the cost of a trial, aside from Provectus's minimal expense to provide PV-10 drug product,
• At a minimum (more than likely) make a one-time payment to Provectus, such as was the case in Bristol-Meyers' collaboration with Celldex Therapeutics, and
• Forego meaningful rights of first somethings, unless the partner fully compensates Provectus for this ask.

I summarized a number of previously announced and/or conducted combination studies in my Combinations (July 24, 2014) news items under the blog's News tab.

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Although Provectus management has understood and communicated the potential for combination therapy involving PV-10 for the treatment of metastatic melanoma, noting this on the 2Q14 conference call (i.e., the Provectus-Pfizer patent application, the SITC 2012 poster presentation), they historically have not prioritized this potential regulatory pathway, and have been disinterested in and unwilling to allocate resources to conduct a typical combination study where companies share trial costs and the "non-CTLA-4/PD-1" (i.e., non-Bristol-Myers or Merck) partner conducts (sponsors) the trial.

There is no certainty a trial comes together, but it would appear Provectus is engaged in the kind of basic or fundamental conversations, data sharing and expectation setting necessary to contemplate a combination study and develop the associated relationship between the parties involved.

The consensus of melanoma key opinion leaders appears to be that “[t]he future lies in combinational approaches with drugs from the new melanoma landscape” (e.g., intralesional therapies, BRAF inhibitors, ipilimumab, anti-PD-1 antibodies). Moffitt Cancer Center's pre-clinical work combining PV-10 with other approved and investigational immunotherapeutic agents more than likely would be, and would have to be, the driving force behind any clinical combination study focused on metastatic melanoma patients with visceral disease (i.e., Stage IV M1b-c). The cancer center already has alluded to the completion and results of this pre-clinical work, which should form the rationale for a future clinical trial or trials, at ASCO 2014 by concluding "IL PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma," and again at the 4th European Post-Chicago Melanoma & Skin Cancer Meeting 2014 by concluding "[p]reclinical data suggest PV-10 would be a good candidate to evaluate in conjunction with available systemic therapies and new agents in development."

I previously wrote about historical pre-clinical and some clinical work on PV-10 in combination with other treatments (systemic chemotherapy [pre-clinical], systemic immunotherapy [pre-clinical], radiotherapy [clinical]) in my "IL PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma" blog post.

A potential clinical trial combining PV-10 with a checkpoint inhibitor should be viewed in the context of other clinical trials and studies Provectus expects  hopes to commence in 2014 and/or 2015:

• Melanoma, PV-10: Phase 3 trial, locally advanced unresectable/unresected cutaneous melanoma, 2H2014,

• Dermatology, PH-10: Phase 1 trial, mechanism of action/feasibility study, 2H2014 (my estimate),

• Liver cancer, PV-10: Phase 2/3 trial, locally advanced, unresectable/unresected liver cancer (my speculation of the trial title), 1H2015 (my estimate); the trial also should include liver tumors caused by primary non-liver cancers (i.e., cancers metastatic to the liver), and

• Melanoma, PV-10: Phase 1 (or 1b)/2 trial, metastatic melanoma, 1H2015 (my estimate, if a deal is consummated in 4Q14); with a trial population similar to that of the ipilimumab+talimogene laherparepvec of mostly Stage IV M1b-c patients

I do not believe a deal between Provectus and a pharmaceutical company (and its checkpoint inhibitor), the first step towards an eventual clinical trial, would be consummated until Moffitt's preclinical combination study data is more broadly communicated. Meaning, neither Bristol-Myers nor Merck, for example, would even contemplate acceding to Provectus deal expectations until and unless Moffitt substantiates their above mentioned conclusions with very compelling data (i.e., together PV-10 makes your drug much better than your drug alone).

I think the venue for the cancer center's communication will be the 29th Annual Meeting of the Society of Immunotherapy for Cancer, November 6-9, 2014. Provectus first addressed combination treatment at the 2012 annual SITC meeting concluding the co-administration of PV-10 immuno-chemoablation with other systemic therapy could yield potent synergy in uninjected tumors.

But, more than just the pre-clinical drug combination study results, I also am very interested in other aspects of Moffitt's work, and Dr. Jeffrey Weber, M.D., Ph.D.'s comprehensive views on the utility and use of PV-10.

First, what is the basis for Weber's comment "PV-10 might offer the perfect way to prime the immune system?" Dr. Weber has said (paraphrasing) the utility of a primer is simply its ability to synergize with the immune agent in question in terms of clinical effect when given prior to the second agent. Moffitt data showing the strength of the systemic responses PV-10 can stimulate (i.e., efficacy of PV-10 plus a checkpoint inhibitor >> efficacy of the checkpoint inhibitor alone) should make this/his point.

Second, what is PV-10's role and participation in each step of the cancer immunity cycle (Chen & Mellman, 2013)? Under the blog's PV-10, and the Cancer Immunity Cycle tab I illustrate PV-10's involvement in steps 1 (release of cancer cell antigens), 2 (cancer antigen presentation), 3 (priming and activation) and 7 (killing of cancer cells). And although Dr. Weber has said (paraphrasing) one should prioritize which steps are the most important (presumably in order to determine how to utilize what agents in combination and why; for example, impacting on endothelial cells have been less promising as a therapeutic than many of the other steps), I'd like to understand Moffitt's view on PV-10's involvement in steps 4 (trafficking of T cells to tumors), 5 (infiltration of T cells into tumors) and 6 (recognition of cancer cells by T cells).

And third, what are Weber's thoughts about PV-10 in the context of or in regards to immune surveillance? Immune surveillance theory is:

The concept that the immune system protects the host against cancer was first posited by Ehrlich in 1909 (1) and modified in the 1950s by Burnet and Thomas (2, 3), who proposed that it was instrumental in eliminating precancerous or cancerous cells, through a “surveillance” function. However, the concept fell out of favor when studies in the 1980s indicated that tumors failed to develop more rapidly in nude mice (which lack T cells and B cells, but not NK cells) than in wild-type mice. It was resurrected in the 1990s, when a body of evidence emerged indicating that immunodeficient mice were at greater risk for spontaneous tumor development (4). These studies led to further refinement of the theory, now referred to as “cancer immunoediting,” encompassing three phases: elimination, equilibrium, and escape. (J Clin Invest. 2007;117(5):1130–1136. doi:10.1172/JCI32136)

In a February article of The American Journal of Managed Care, Weber said:

"Well, the Holy Grail of cancer immunology is to create a cancer vaccine. Provenge was the first and only cancer vaccine that was ever approved. But that is truly the mantra, that is, the immune system is the ultimate way to perform targeted therapy. So immunotherapy is targeted therapy, and its hallmark is memory." {Underlined emphasis is mine} 

And: "There are certainly data to suggest that this idea of immune surveillance is indeed valid. On the other hand, people on immunosuppressants don’t always present with 30 different types of solid tumors. Transplant patients often develop squamous skin cancers, especially virally related squamous skin cancers. So there are data to suggest that we always have immune surveillance to prevent cancer from developing." 

And: "You can divide immunotherapies into 4 or 5 categories: these include chemicals like cytokines; antibodies…cells, which are not really well developed; vaccines, which is always the Holy Grail to try to vaccinate someone against his or her own cancer. You’ve got 1 approved vaccine. One of the antibodies, which are the most exciting and promising, is approved. That’s ipilimumab, the anti-CTLA4 antibody. In terms of the cytokines, in 1996 and 1998 IL-2, interleukin-2, was approved for kidney cancer and for melanoma. The cell therapy is immature, and you will hear a lot more about the antibodies coming up in the next couple of years." {Underlined emphasis is mine} 

Recall that Moffitt said, following their initial murine model work, that:

"These murine studies confirm that PV-10 chemoablation results in both a direct effect on injected lesions as well as a systemic response that leads to regression of uninjected subcutaneous and lung lesions. Intralesional PV-10 treatment leads to the induction of tumor-specific immunity." (AACR 2013) {Underlined emphasis is mine} 

And that Provectus concluded at SITC 2012, by virtue of murine model work:

Chemoablation with PV-10 results in the induction of tumor-specific immunity. Immunodeficient mice exhibited no anti-tumor effect on re-challenge. Adoptive transfer of immunity only occurred following chemoablation in donor mice. Tumor-specific, long-term immunity and adoptive transfer implicate immune cell mediation. This immuno-chemoablative response to PV-10 is tantamount to “in situ vaccination.” (SITC 2012) {Underlined emphasis is mine} 

“PV-10 might offer the perfect way to prime the immune system”

Two articles on PV-10, and Provectus and Moffitt ASCO 2014 posters came out today: Provectus outlines path forward for PV-10 and PV-10 produced complete response in 50% of advanced melanoma patients. The articles are variations on the same themes and quotes.

For a moment, think about this verbiage: "The study showed that following intralesional PV-10, both PV-10-injected and uninjected study lesions had pathologic complete response (pCR) in four of the eight patients and that all eight patients exhibited at least partial regression of the injected lesion," and "It is noteworthy that six of eight patients had metastatic disease refractory to previous ipilimumab, anti PD-1 and/or vemura[f]enib therapy." Said another way, perhaps, Moffitt achieved 100% "objective response" in injected lesions and at least 50% in uninjected lesions (there is no mention in the article about whether there was partial regression in the uninjected lesions of the four patients who did not achieve pCR.

Interestingly, Moffitt's Dr. Jeffrey Weber, M.D., Ph.D. said “This data provides more and more evidence that you are altering both local and systemic immunity in a positive way. It also provides a rationale for combination trials of PV-10 with check point protein inhibitors, such as ipilimumab, pembrolizumab and nivolumab. PV-10 might offer the perfect way to prime the immune system” {bold emphasis is mine}.

In April 2014 Dr. Weber said: "“Checkpoint inhibitors are quickly becoming the standard of care for metastatic melanoma, but 50 to 60% percent of patients do not benefit from these agents." The relevancy of PV-10 and other intralesional ("IL") agents to metastatic disease is their potential to make the combination (of the intralesional agent and the checkpoint inhibitor) better for patient in terms of efficacy, safety and tolerability, presumably more so than combinations of checkpoint inhibitors and other checkpoint inhibitors, or drug XYZ and drug ABC.

For example: "The combination of anti-CTLA-4 immunotherapy with agents that prime immune responses have been successfully employed in multiple tumor models and highlight the importance of immune priming for successful anti-CTLA-4 immunotherapy" (Source: Joseph Grosso and Maria Jure-Kunkel, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey, 2013). Or: "An immune system primed to properly identify and destroy tumor cells would eliminate errant cells in nearby lymph nodes and distant metastases, thus solving one of the most difficult problems in cancer therapy—the treatment of patients with late-stage disease (stage III or IV)" (Source: Jedd Wolchok, Memorial Sloan-Kettering Cancer Center, 2008). Or the 32 times "priming" is mentioned in Combining immunotherapy and targeted therapies in cancer treatment (Matthew Vanneman and Glenn Dranoff, Nature, 2012).

IL agents can prime the immune system. See PV-10 & Amgen's Talimogene Laherparepvec  (June 9, 2014) under the blog's News tab. According to Weber, "PV-10 might offer the perfect way to prime the immune system." For metasatic melanoma, does PV-10 make ipilimumab (Yervoy), pembrolizumab (MK-3475) and nivolumab relevant?