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.

$PVCT's PV-10: Resistance is Futile

GSK gets 2 cancer pills approved, but a deeper question is left unanswered, by Marc Iskowitz at Medical Marketing & Media (italicized quotes below, without attribution, are from the above article).

Before we excessively hail the arrival of GlaxoSmithKline's Tafinlar (dabrafenib) and Mekinist (trametinib), let's be thoughtful about their approval tells us (or, frankly, does not).

"Two targeted cancer pills that received the FDA's nod yesterday offer physicians another set of weapons to fight the disease. They also highlight a difficulty that has plagued recent advances—the body's resistance to personalized drugs."

"The approvals add to the excitement going into the American Society of Clinical Oncology (ASCO) annual meeting, which gets under way tomorrow in Chicago. However, they also underscore a difficulty. As drug makers advance in identifying targeted therapies for particular biomarker segments, in many cases where they've developed such a treatment, the cancer comes back months later."

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

"Scientists are realizing that “targeted therapies do not lead to long-term tumor control,” said Richard Wagner, PhD, a VP at Kantar Health. “This is a problem that shadows progress.” One example is Zelboraf, the drug approved in 2011 which targets the roughly 50% of melanoma patients whose tumors carry the BRAF gene mutation. In virtually all of these patients, the tumor starts to progress again in about five months."

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


"But trying to find ways to prevent the development of resistance with targeted therapies has become another front in the war on cancer. It's also among the reasons why there is so much excitement about the immuno-oncology agents from BMS (nivolumab), Merck (MK-3475) and Roche (MPDL3280) that offer a third approach to treating the disease, beyond targeted therapies and conventional chemotherapy."

So, the industry is getting there. Slowly. Recall Craig et al.'s conclusion at SITC:




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

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

Moffitt, however, through their focus on adoptive T cell immunotherapy, believes PV-10 induces better T cells, and thus T cell activation for very specific tumor targeting. Moffitt's AACR poster concluded PV-10 induced a systemic anti-tumor immune response in murine models of melanoma and breast cancer. Moffitt has concluded the same, through its murine work, in lung cancer, colorectal cancer, pancreatic cancer and liver cancer.

(Source withheld, 2009) There have been well documented but exceedingly rare cases of spontaneous or post-infection remissions in melanoma that appear to be immunologically mediated. There is a correlation between treatment-associated autoimmune depigmentation, or vitiligo, and favorable melanoma outcomes. Regression of uninjected melanoma modules after intralesional BCG therapy had been demonstrated.

Results with conventional therapy for metastatic melanoma up to that point remained poor. Melanoma patients at high risk of recurrence are readily identifiable. Tumor-induced immunosuppression increases with tumor burden. Immunotherapy should be more effective the earlier it is applied. 

But there are major obstacles to overcome: patient heterogeneity (variable outcomes for patients within similar stages, HLA haplotype differences), tumor antigenic heterogeneity (not all tumors express the same antigens), antigen loss (most immunogenic proteins are not essential to survival), tumor-induced immunosuppression, and the length of time needed for an immune response.


A weak or partial immune response to the tumor selects for more virulent tumor cells to survive, akin to antibiotic resistance in microbial infections. Vaccines are inducing “tolerance” by repeated exposure to antigen, convincing the immune system not to react to tumor-associated antigens and/or stimulating the generation of “suppressor” cells.

Tumor heterogeneity is a critical problem. In any given cell there are, say, 15,000 unique mRNAs at any given second. A few seconds later, illustratively, 15,000 new ones. There are, for example, at least 15,000 to 20,000 unique proteins on a membrane surface at any one time. These change continuously. Does picking one of them to form the basis of a cancer vaccine make sense? Does targeting a specific antigen as a holistic solution make sense?

Heterogeneity is so wide, trying to target a specific antigen might be tough if not hopeless task. A needle in a haystack? Maybe a needle in an entire whole galaxy.

Treating as many tumors as you can with PV-10 intratumorally achieves two significant positive outcomes. First, you lower the patient's overall tumor burden so as to allow the immune system to work better. Second, you allow more of the heterogeneous antigens (from the injected heterogeneous tumor) to be seen by the immune system. The more tumors treated by PV-10 the better.

"Speaking as part of a panel assembled by Kantar Health, King said that what he thinks is compelling about the experimental agents is the "ability to get treated for a year and walk away for three to five years.""

PV-10 is displaying impressive durable response in patients. Recall, via Provectus News, management informed shareholders and others about a Practical Dermatology article on PV-10 that included comments from principal investigator Dr. Sanjiv Agarwala, MD: "Since those data were first reported, “There are now data for longer follow-up periods that show those initial results are holding up,” says Sanjiv S. Agarwala, MD, Professor of Medicine at Temple University School of Medicine in Philadelphia and Chief, Oncology & Hematology at St. Luke’s Cancer Center in Bethlehem, PA."

As a monotherapy, clinicians want to use PV-10 before surgery when the immune system is not, moderately or less severely compromised, by itself after surgery too, and in very late stage disease patients with other agents when the immune system is overwhelmed and severely compromised.

PV-10 has a very good answer for this deeper question that other agents, including CTLA-4, PD-1, PDL-1 and OXO-40, have yet to answer as well.