November 1, 2014

Florey, Chain & Heatley⎟Coley⎟sort of, maybe, possibly, conceivably, probably...

‘‘Drugs can only repress symptoms: they cannot eradicate disease. The true remedy for all diseases is Nature’s remedy .... There is at bottom only one genuinely scientific treatment for all diseases, and that is to stimulate the phagocytes. Stimulate the phagocytes. Drugs are a delusion.’’ -- Counsel of physician Sir Bloomfield Bonington in George Bernard Shaw’s 1906 play The Doctor’s Dilemma; the use of the quote comes from the article Dr William Coley and tumour regression: a place in history or in the future by Hoption Cann et al.
▸ Alexander Fleming discovered penicillin in 1928, while the discovery of penicillin's medical use was established more than a decade later by Howard Florey, Ernst Chain and Norman Heatley (source link: Wikipedia).

Penicillin was/is a discovery that changed the course of medicine.

▸ William Coley is a pioneer of cancer immunotherapy (late 1800s), and considered by many to be the "Father of Immunotherapy." According to Wikipedia (see immediately prior link):
"Coley developed the theory that post-surgical infections had helped patients to recover better from their cancer by provoking an immune response. He began to experiment by deliberately causing this phenomenon, injecting bacteria directly into people being treated – but because this had the adverse effect of causing infection he then switched to using dead bacteria."
Hoption Cann et al. (link at the top of the post) write about Coley's work:
"Coley considered several points crucial to a patient’s survival. First and foremost was to imitate a naturally occurring acute infection, and thus, inducing a fever was essential. Injections were optimally administered daily (or every other day) for the first month or two. To avoid immune tolerance to the vaccine, the dosage was gradually increased over time (depending on patient response). The vaccine was injected directly into the primary tumour and metastases, when accessible. Finally, a minimum six month course of weekly injections was followed to prevent disease recurrence." {Underlined emphasis is mine.}
Coley injected the bacteria/vaccine/toxins into cancerous tumors and cancer metastases.

▸ Why then, when writing about cancer immunotherapy and associated approved and investigational checkpoint blockade drugs like Yervoy (anti-CTLA-4, Bristol-Myers), Keytruda (anti-PD-1, Merck), Opdivo (anti-PD-1, Bristol-Myers), MPDL3280A (anti-PD-L1, Roche/Genentech), MEDI4736 (anti-PD-L1, AstraZeneca/MedImmune), etc., do some folks include what seems like obligatory yet obtuse nods to Coley? Google, for example, coley immunotherapy pd-1.

Coley's vaccine and these inhibitors both engage the immune system. But although the mechanism of action of Coley's vaccine (or Coley's toxins as it also was known) was and remains unknown, it is believed the approach led to specific and non-specific immune responses (paragraph source/sentence taken from: Rational approaches to human cancer immunotherapy, Davis et al.). Interestingly, according to Davis et al.'s article, Coley's injected-bacteria-into-accessible-tumors-and-metastases was, "[a]s late as 1934, “Coley’s toxins” was the only known systemic treatment for cancer" (article footnote). {Underlined emphasis is mine.} A treatment injected into tumors that generates an immune response is called a systemic treatment for cancer. Interesting...

Checkpoint blockade therapeutic agents are non-specific immunotherapies. "Non-specific immunotherapies don’t target cancer cells specifically. They stimulate the immune system in a more general way..."

CTLA-4s, PD-1s, PD-L1s, etc. are non-specific immunotherapies. 

"According to a 1965 article that was published in A Cancer Journal for Clinicians (1):

“In 1952, a bibliography of the literature, and, in 1953, a report on 30 inoperable cases which had been treated by Coley's mixed toxins and had survived thereafter for periods of from 1 to 47 years (20 cases had a survival of over 20 years) were published. The report is said to be based on a comparative analysis of over 1,200 cases treated with Coley's toxins, and 300 cases in which intercurrent infections played a part. Over 270  cases were said to have shown complete regression of the tumor, but the 30 inoperable cases were selected for the report because the diagnoses had been confirmed by microscopic examination, and some information on their subsequent history was available. Of the 30 tumors, 7 were classified as carcinoma, 19 as various types of sarcoma, 2 as malignant melanoma, and 2 as giant cell tumors.”

A complete response rate of 22% (270 out of 1200) was impressive by the standards of the 1960's and today. But, despite these results, the article states that the, “American Cancer Society has found no evidence that treatment with Coley's mixed toxins results in any objective benefit in the treatment of cancer in human beings.”  It is difficult to reconcile this conclusion with the results cited in the same article. Perhaps the results were simply not believed as they were authored by Mrs. Helen Coley Nauts, Executive Director of the New York Cancer Research Institute. Mrs. Nauts was the daughter of William Coley." (paragraph source link) {Underlined emphasis is mine.}

Coley's approach generated notable complete responses.

▸ Which brings us to a chicken-and-egg question. Which comes first, the complete response, or the immune response? For PV-10, successfully generating a complete response leads to a good to great immune response.

Per medical writer Walter Alexander's recent article PV-10 in Metastatic Melanoma: Rapid Responses Led Phase 3 (he's written about PV-10 before, including PV-10 Moves Forward):
The high-percent response rates in bystander lesions underscored the importance of elucidating the mechanism underlying PV-10's activity. That meant going back to bench investigations. The operant question for researchers, according to Shari A. Pilon-Thomas, PhD, Moffitt Cancer Center Immunology Program, was: "Is it just because you inject the drug and it goes everywhere and then kills tumor cells at other sites? Or is injecting PV-10 inducing a T-cell response, such that T-cells travel throughout the body and kill tumors in their various locations?
In a poster presentation at the 2013 meeting of the American Association of Cancer Research, she pointed to evidence suggesting that an immune-mediated process underlies PV-10 responses in untreated lesions. First, responses in untreated lesions occurred only when responses had occurred in injected lesions, and second, responses in bystander lesions typically were delayed in comparison with responses in injected lesions, Dr Pilon-Thomas noted. 
Dr Pilon-Thomas has previously shown in murine models that induced flank tumors treated with PV-10, as compared with placebo, were about a third of the size, and bystander lesions were about 30% smaller. At the same time, concentrations of interferon-gamma, a cytokine critical for innate and adaptive immunity (including tumor control) and for activating macrophages, were increased more than fivefold. 
These findings, along with those from other studies, led Dr Pilon-Thomas to conclude, "We think that when you inject PV-10 into a tumor, it destroys the tumor, releasing tumor fragments that are then taken up by immune cells. The immune cells travel to the lymph nodes where they 'educate' or activate T-cells, which can in turn travel anywhere in the body." 
Her research also showed that PV-10-induced immunity is tumor specific.
Further evidence of immune responses induced by PV-10 come from another study conducted at the Moffitt Cancer Center, this time involving eight patients with dermal and/or subcutaneous metastatic melanoma. The findings, presented at this year's ASCO annual meeting in a highlighted poster session by Amod Sarnaik, MD, a surgical oncologist at the Moffitt Cancer Center, showed that intralesional PV-10 was associated with a significant increase (P = .03) in circulating cytotoxic CD8+ T-cells, a potential mechanism for a tumor-specific immunologic effect secondary to tumor ablation. 
In this study of eight patients, each patient had two study lesions that were sampled by biopsy before treatment; one of the two lesions was injected with intralesional PV-10, and then both residual sites were completely excised 1 to 2 weeks after PV-10 injection. Tumors were compared before and after treatment to determine pathologic complete response (pCR). 
PV-10 resulted in pCR in the posttreatment biopsy specimens of both PV-10-injected and uninjected study lesions in four of the eight patients, and all eight exhibited at least partial regression of the injected lesion. 
Six of these eight patients had metastatic disease that was refractory to previous treatment with immunologics (ipilimumab [Yervoy, Bristol-Meyers Squibb Company] and anti-PD-1 therapy) and BRAF-mutation inhibitor (vemurafenib [Zelboraf, Hoffman-La Roche]). After PV-10, four of these six patients had pCRs in both the injected and uninjected lesions. {Underlined emphasis is mine.}
PV-10 generates a complete response in order to generate/which is followed by an immune response.

▸ On Wednesday of this past week, Forbes contributor Jon Fortenbury wrote about PV-10 and Provectus in a post entitled A New Cancer Drug Worked In Over 50% Of Patients In A Phase II Trial. On Thursday, he updated the post to " include comments from an outside expert and the company's response to his criticism." Forbes staff member and editor of the section Matthew Herper later weighed in under the Comments section with:
Click to enlarge.
On Thursday, Bristol-Myers issued a press release about PD-1 Opdivo's results for heavily pre-treated advanced squamous cell non-small cell lung cancer, generating a a Bloomberg headline: Bristol-Myers Immune Drug Improves Lung Cancer Survival:
An estimated 41 percent of the advanced lung cancer patients taking Opdivo were alive after a year on the drug, compared with 5.5 percent to 18 percent of these patients who historically have survived over that time-frame, Bristol-Myers said today in a statement. About 15 percent of the 117 patients in the mid-stage study responded to the treatment, one of a new class of cancer therapies that harnesses the body’s immune system to attack the disease.
"[P]atients in the mid-stage study responded to the treatment" above refers to objective response. If Opdivo were where we need to be in terms of better helping or utilizing the immune system, wouldn't Bristol-Myers have heralded complete response (objective response = complete response + partial response) more. The pharmaceutical company surely would have if the trial's CR were notable.

Certainly what was notable was the improved overall survival (the quote's "the advanced lung cancer patients taking Opdivo were alive after a year on the drug") compared to historical survival figures.

As for Herper, other journalists, commentators and opiners, aside from better survival figures that are of course very good things (longer survival is better than no or shorter survival), why do they not mention or say in the same breath that generations of immunco-oncology therapeutics agents that have come (Yervoy), are here (Keytruda, Opdivo), and are to come (MPDL3280A, MEDI4736) have not had/do not have notable or memorable complete responses?

Partial response, good. Complete response, best.

▸ To be fair, Herper, who probably has covered biotechnology companies and the subject of oncology longer than I've held Provectus shares, and who also believes this is biology's century, may not understand the conflation Fortenbury's article, upon further editing and insertion of the "outside expert's" quote, managed to achieve.

The article described Provectus' melanoma Phase 2 trial results and, in particular, the sub-group of patients who had all of their disease treated (i.e., injected with PV-10). Why was/is this relevant? As Fortenbury writes, "If PV-10, when injected in all the cancerous lesions of a melanoma patient for longer than 16 weeks, goes on to produce positive results in the next phase, it just may be a viable treatment option for many patients with aggressive, late-stage, locally advanced melanoma." The target population of the company's upcoming pivotal Phase 3 trial are patients with un-resectable locally advanced cutaneous melanoma, which means the melanoma (i) cannot be removed by surgery (non- or un-resectable), (ii) is located in or just under the skin (cutaneous and subcutaneous, respectively), and (iii) has not metastasized to distant sites like the lungs, liver or brain.

These patients need better options, like Eric, "...patients clearly need more options: single agent options and more options for finding successful combinations that can truly change the course of this vicious disease," and Dr. Agarwala, "I think it will be an option for many patients who have a cancer disease that’s localized or regional," were quoted in the Forbes article.

Locally advanced cutaneous (or subcutaneous) melanoma = Melanoma that has not spread or metastasized.

This is worth repeating: The upcoming pivotal Phase 3 trial will comprise Stage III patients. The disease in Stage III has not spread. Patients in which the disease has spread are Stage IV patients.

Stage III ≠ Stage IV.

▸ Conflation in the article occurs when Herper asks Fortenbury to have an "outside expert" opine: PD-1 Keytruda clinical investigator and UCLA Jonsson Comprehensive Cancer Center medical oncologist with multiple clinical interests Dr. John Glaspy, M.D., MPH is quoted. Medical oncologists (like Glaspy and PV-10 principal investigator Agarwala) see mainly stage IV patients, while surgical oncologists (like PV-10 principal investigator Dr. Merrick Ross, M.D. from MD Anderson Cancer Center ) see mostly stage III patients.

The data Fortenbury's article highlights show PV-10 as a monotherapy could be an important option for patients with locally advanced cutaneous melanoma. The FDA also appears to be considering this topic too. It announced on October 8th that "melanoma, specifically unresectable loco-regional disease" was a disease candidate for public comment. See Prescription Drug User Fee Act Patient-Focused Drug Development; Request for Comments (October 8, 2014) on the blog's News page.

Locally advanced cutaneous melanoma = Stage III = Melanoma disease has not spread  Stage IV = Metastatic melanoma with visceral disease and heavy tumor burden.

▸ Glaspy's words in the article:
John Glaspy, an oncology professor at UCLA, says that “it’s not clear” whether the result are important. If they are talking about lesions that were not directly injected with the drug, the results would be meaningful. “If they are talking about the injected lesion, not so much,” Glaspy says. 
When asked about it, he repeated: “Like I said, these SQ melanomas are an indolent disease, and it is not a big deal if you inject them and they regress.  I don’t think you have any evidence that anybody is cured.” {Underlined emphasis is mine}
It is not a big deal if tumors regress. They need to be destroyed. That's the big deal. Fifty percent of patients in the sub-group of Provectus' Phase 2 trial who had all of their disease treated achieved a complete response (total cancer disappearance) during a treatment period that was just 16 weeks.

Yervoy, Keytruda, Opdivo, MPDL3280A and MEDI4736 are far from curing melanoma patients because they are not achieving notable or memorable complete responses.

Partial response, not a big deal. Complete response, cured?

▸ One simple but I don't believe an over-simplistic way of looking at the situation could be surgical oncologists look at melanoma (and cancer at large) when it is first diagnosed or has not spread beyond control or has not metastasized. Medical oncologists look at melanoma (and cancer at large) when it has spread or looks like it is beyond control.

Surgical ocologists: PV-10. Medical oncologists: PV-10 + something else.

▸ Eric, in regards to, I believe, late-stage (Stage IV) patients (patients with distant metastases), in the Forbes article, "...more options for finding successful combinations that can truly change the course of this vicious disease," undoubtedly would have told Fortenbury about Moffitt Cancer Center presenting pre-clinical data on these combinations (i.e., PV-10 + [insert checkpoint blockade agent]) at the annual meeting of the Society for Immunotherapy of Cancer ("SITC") next week.

The idea behind combining PV-10 and a checkpoint blockader may be to generate both the specific and non-specific kinds or types of immune responses Coley's vaccine/toxins were believed to have generated. The goal of employing these kinds of combinations, to battle melanoma (cancer) once it has spread to distant sites, may be to generate both specific and non-specific immune responses.

Stage IV melanoma: PV-10 + one of (Yervoy, Keytruda, Opdivo, MPDL3280A, MEDI4736)

Yervoy, Keytruda, Opdivo, MPDL3280A, and MEDI4736 need help.

▸ Roche's Genentech's Dr. Daniel Chen, M.D., Ph.D. quoted Roche's Genentech's Dr. Ira Mellman, M.D., both co-authors of Oncology Meets Immunology: The Cancer-Immunity Cycle, at ESMO 2014:
Click to enlarge. Screen shot source: Biotech Strategy Blog.
The ultimate goal of cancer treatments is to completely eliminate a tumor. Complete response.

▸ Which brings me back to where I started this post, with Florey, Chain & Heatley, and Coley.

Dees, Scott and Wachter did not discover rose bengal. It can be traced back to Basel, Switzerland in 1882 when a German patent was granted to Ghnem for a new family of wool dyes. Dees et al. were not the first to use rose bengal in an oncology setting. Japanese researchers Ito and Watanabe did so in 1986. Rose bengal's therapeutic benefit is unrealized until a sufficient quantity is administered.

Craig postulated intratumoral injection, and thus the delivery of the drug via the tumor or lesion, was key. He thought it was critically important to the eventual immune response that PV-10 (rose bengal) be injected into a cancerous tumor or cancer metastases.

What kind of therapy is PV-10? From a 2013 Cancer Watch article entitled Back to Phase 1: Understanding Systemic Effects of PV-10:
Echoing [Moffitt Cancer Center's] Dr. Sarnaik, Eric Wachter, PhD, Provectus chief technology officer, said that he hopes that the findings of Dr. Sarnaik’s study will point toward rational judgments about combining PV-10 with other documented therapies. “We then might want to try two or more orthogonal therapies to stress tumor cells from several different angles simultaneously, for example an immune therapy plus a metabolic therapy (e.g., a kinase inhibitor), or in a rationally designed sequence.” In a hepatocellular carcinoma model, he added, PV-10 showed significant potential for synergy with 5-fluorouracil. Provectus recently initiated clinical testing of PV-10 with the multikinase inhibitor sorafenib, again bringing in two therapies with divergent mechanisms of action. 
Which category does PV-10 fall into? “I think we are getting a clearer picture of how it might be classified, but it has features of several previously unrelated categories, such as of adoptive cell transfer and vaccination,” Dr. Wachter said. “PV-10 initially reduces tumor burden through chemoablation—but then activates the immune system bringing in capacities completely orthogonal to the ablative tumor destruction,” he added. 
“Amod Sarnaik’s work may give us the molecular basis for closing the loop on one of the founding concepts for going into the clinic in the first place,” Dr. Wachter commented. “Back in the preclinical days at Provectus, Craig Dees, PhD, theorized that ablation of tumors with PV-10 might lead to unmasking of tumor antigenic material. I don’t think he anticipated that it would work as well as it does.” {Underlined emphasis is mine.}
Vaccines are too specific. They facilitate the expression of only one antigen. Vaccines are antigen specific.

CTLA-4, PD-1 and PD-L1 therapeutic agents are not specific enough. They do not facilitate the expression of enough antigens.

PV-10 ablation of tumors presumably leads to the generation of antigens that are presented to the immune system in (i) as large a number as possible, (ii) pristine and not un- or non-denatured shape, (iii) whole pieces and not fragments, (iv) correct conformation/the right shape, and (iv) the right context.

PV-10: A paradigm shift in the treatment of cancer

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