The Early Obsolescence of Checkpoint Inhibitors

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Take as a starting point Inman et al.’s 2007 article entitled Costimulation, coinhibition and cancer, and their statement therein: (underlined emphasis is mine):

“If sufficient co-stimulation is provided in the presence of adequate tumor-associated antigenic stimulation, the immune system will act against tumor antigen and, thus, destroy early tumors before they become fully established. Contrarily, if co-inhibitory signaling dominates, the immune system will be tolerized to tumor antigens, and the tumor will be permitted to grow unfettered and unmolested by the immune system. If neither co-stimulatory nor co-inhibitory signals dominate, the adaptive immune system may remain in a tenuous state of equilibrium, militating against tumor outgrowth with varying degrees of success.”

The essence of the authors’ view might be that the immune system is capable of decisively acting against cancer only in the situation where or circumstance that co-stimulation dominates co-inhibition. Take also as context to this starting point, however, that what we don’t know about the immune system probably dwarfs what we know about it.

The notion of “releasing the brakes” in the medical literature and mainstream press describes the approach of inhibiting cancer’s ability to suppress or block the body’s immune system from acting, and thus to evade attack. Although possibly coined in the early-2000s (see, for example, Tirapu et al.’s 2002 article entitled Effective tumor immunotherapy: start the engine, release the brakes, step on the gas pedal,...and get ready to face autoimmunity), use of the releasing-the-brakes phrase may have grown more widespread starting in the late-2000s and around the time of Dr. James Allison, Ph.D’s seminal work of blocking (inhibiting) the CTLA-4 protein receptor (using Bristol-Myers’ ipilimumab) and, later, the follow-up scientific exploration of blocking (inhibiting) PD-1 and PD-L1 ligands too (and associated PD-1 therapeutics pembrolizumab and nivolumab, for example, from Merck and Bristol-Myers, respectively).

Medical literature has more sparsely touched on, and mainstream press much less so, the other two components of the get-the-car-moving analogy (where the car is the immune system), “starting the engine” and “stepping on the gas pedal,” where these phrases relate to different aspects of stimulating the body’s immune system.

Possibly over-using the car analogy further, with the potential risk of over-simplifying it inappropriately, consider T cell immunity as a car at rest. More immunogenic tumors and their associated cancers like melanoma are like a car sitting on a slight incline. Release its brakes by treating the tumors (and thus the cancer) with checkpoint inhibitors, and the car may roll forward move some distance, notable or otherwise. With other less or non-immunogenic cancers, think of the car as sitting on a flat surface. Releasing the brakes does not enable the car to move any meaningful distance, if at all.

If you want to get the car to really move, you have to start its engine, and then step on its gas pedal. Releasing the brakes might help the car move farther and faster, but it also is quite possible the car may be able to move sufficiently without the need for further action other than to start its engine and/or stepping on its gas pedal.

The continued use of get-the-car-moving analogy of course requires the assumption the car can drive by itself; that is, the immune system can handle its own business once it has been started, and is appropriately up and running from stepping on the gas pedal.

Now consider Winograd et al.’s 2015 article entitled Induction of T cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. In particular, note the underlined sentences (my emphasis) from the article’s abstract:

“Disabling the function of immune checkpoint molecules can unlock T cell immunity against cancer, yet despite remarkable clinical success with monoclonal antibodies (mAb) that block PD-1 or CTLA-4 resistance remains common and essentially unexplained. To date, pancreatic carcinoma is fully refractory to these antibodies. Here, using a genetically engineered mouse model of pancreatic ductal adenocarcinoma in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients; however, tumor PD-L1 was found to be independent of IFN-γin this model. Tumor T cells expressed PD-1 as prominently as T cells from chronically infected mice, but treatment with PD-1 mAb, with or without CTLA-4 mAb, failed in well-established tumors, recapitulating clinical results. Agonist CD40 mAb with chemotherapy induced T cell immunity and reversed the complete resistance of pancreatic tumors to PD-1 and CTLA-4. The combination of αCD40/chemotherapy plus PD-1 and/or CTLA-4 induced regression of subcutaneous tumors, improved overall survival, and confered curative protection from multiple rechallenges, consistent with immune memory not otherwise achievable. Combinatorial treatment nearly doubled survival of mice with spontaneous pancreatic cancers although no cures were observed. Our findings suggest that in pancreatic carcinoma, a non-immunogenic tumor, baseline refractoriness to checkpoint inhibitors can be rescued by the priming of a T cell response with αCD40/chemotherapy.”

CD40 is a co-stimulatory protein, while chemotherapy has been understood to act in a stimulatory fashion through the subsequent release of cancer antigens.

Achieving T cell immunity almost if not actually by definition should mean overcoming resistance to cancer, thus overcoming checkpoint blockade and mitigating the need to artificially release the brakes.

Should stimulation via stimulatory therapeutics and therapies start the engine and enables the gas pedal to be stepped on sufficiently and appropriately (i.e., with minimal or manageable side effects or adverse events) so as to achieve T cell immunity, brakes may not be necessary once the car is moving (in context, and given the car [the immune system] can drive itself and not careen off the road because it then should know what it is doing).

Over time, however, road friction may start slowing the car down to the point where waning immunosurveillance (the immune system recognizing and eliminating continuously arising cancerous cells) no longer can protect the patient from relapse (analogous to how waning varicella zoster antibody titers may result in a bout of shingles). Keeping the brakes disengaged, especially with non-immunogenic tumors, should have some role going forward, making Merck, Bristol-Myers, Roche, AstraZeneca, Pfizer and other companies’ checkpoint inhibitors not necessarily obsolete as much as persnickety.

Bristol-Myers vs. The Field (ex-Provectus)

Last week Bristol-Myers filed a lawsuit against Merck over [anti-]PD-1 agent pembrolizumab (trade name Keytruda), which was approved last week by the FDA for late-stage or metastatic melanoma.

Specifically, Bristol-Myers claims that Merck is violating the patent on its Opdivo mediation for tackling melanoma, which was recently approved in Japan and became the first so-called PD-1 inhibitor to win regulatory backing anywhere. A PD-1 inhibitor blocks a protein that acts as a brake on certain immune system cells and prevents them from attacking healthy tissue. (Bristol-Myers Sues Merck Over a Patent on its new Cancer Drug, The Wall Street Journal, September 8, 2014)

Merck disclosed PD-1 antibody patent oppositions and litigation, at the time in Europe, in its 10-Q filing for the period ending June 30, 2014 (see page 22):

As previously disclosed, Ono Pharmaceutical Co. (“Ono”) has a European patent (EP 1 537 878) (“’878”) that broadly claims the use of an anti-PD-1 antibody, such as the Company’s immunotherapy, pembrolizumab (MK-3475), for the treatment of cancer. Ono has previously licensed its commercial rights to an anti-PD-1 antibody to Bristol-Myers Squibb (“BMS”) in certain markets. The Company believes that the ‘878 patent is invalid and filed an opposition in the European Patent Office (the “EPO”) seeking its revocation. In June 2014, the Opposition Division of the EPO found the claims in the ‘878 patent are valid. The Company expects to receive the Opposition Division’s written opinion in the third quarter of 2014, after which it will begin the appeal process. {Underlined emphasis is mine}

As FiercePharma's Tracy Staton writes: "The lawsuit asks for damages, but more importantly, asks the court to declare that Merck infringes that PD-1 patent. Such a decision would bolster Bristol-Myers and Ono's argument that they are owed royalties on sales of rival PD-1 drugs."

As I wrote in my Why Keytruda's approval is a good thing for PV-10 (September 8, 2014) news item under the blog's News tab:

KOLs see PD-1s as treating the bulk of late stage cancer. Key opinion leaders ("KOLs") see PD-1s, which fall under the category of checkpoint protein inhibitors that also include CTLA-4 and PD-L-1 agents, as an improvement over CTLA-4 agents like approved ipilimumab (trade name Yervoy) and tremelimumab. KOLs will use PD-1s to treat as many indications as they can scientifically support. Abstracts of Merck oncology-sponsored pembrolizumab studies being presented at ESMO 2014 in late-September, for example, include bladder and gastric cancer, advanced melanoma, non-small cell lung cancer ("NSCLC"), and head and neck cancer.

Bristol-Myers and Merck's PD-1s are projected to play key roles in the supposed several tens of billions of dollars equity research analysts estimate will be derived from the immuno-oncology addressable market.

But KOLs believe the more dominant use of PD-1s will come from combining them with other drugs to treat late-stage cancer, rather than strictly using them as monotherapies. I summarized 14 previously announced and/or conducted combination studies below, and first in my Combinations (July 24, 2014) news items under the blog's News tab.

Click to enlarge.

Click to enlarge.

Bristol-Myers, however, has its bases covered with a combination therapy patent that covers PD-1s and other therapeutic compounds and compound categories. Again, Merck challenged it, noting such in the above mentioned quarterly filing:

On April 30, 2014, the Company, and three other companies, opposed another European patent (EP 2 161 336) (“’336”) owned by BMS and Ono that it believes is invalid. The ‘336 patent, if valid, broadly claims anti-PD-1 antibodies that could include pembrolizumab. {Underlined emphasis is mine.}

Bristol-Myers and Ono Pharmaceutical's '878 patent covers PD-1s as monotherapies.

Bristol-Myers and Ono's '336 patent covers PD-1s in combination with other agents, and appears to include a number of companies' products including Amgen's oncolytic virus and intralesional agent talimogene laherparepvec ("T-Vec"). T-Vec had been combined with Bristol-Myer's approved [anti-]CTLA-4 agent ipilimumab (trade name Yervoy), the results of which were presented at ASCO 2014. Amgen and Merck plan to combine T-Vec with Keytruda in a trial slated to start later this year.

A Big Pharma (BMS) with a market capitalization of about $85 billion (per Yahoo! Finance as of yesterday's close) battling one (MRK) with a market cap of about $176 billion. Afterall, in 2013, Citi analyst Andrew Baum estimated potential annual immuno-oncology-related sales to be $35 billion by 2023 (cough). Titans battling...

It does not appear PV-10 is covered by Bristol-Myers and Ono Pharmaceutical's '336 combination therapy patent. PD-1s in combination with PV-10 apparently are, however, covered by Provectus' combination therapy patent application (20120263677 ["'677"]) that it jointly filed with Pfizer (through an expansion, or continuation in part, of Claim #1) in 2012. Pfizer and Provectus would share CTLA-4-related combination therapy sales revenue via the '667 patent application if/when issued, but the former has no claim in the patent app on economics derived from PD-1-related combination therapy sales.

Whether the '878 monotherapy patent ultimately prevails -- that is, whether Merck is violating the patent for tackling cancer (see paragraph 047) -- is Merck's problem, and the Big Pharma eventually may elect to direct royalties Bristol-Myers and Ono's way(s).

Merck could, however, circumvent paying the other parties by meaningfully combining pembrolizumab/Keytruda with PV-10. Directionally speaking, immuno oncology is trending towards combination therapies for late-stage cancer treatment. Strategically, PV-10 should permit Merck's PD-1 to achieve greater tumor destruction and immunological signaling, and be the perfect front end for an immunologic back-end like Keytruda for the ultimate and better benefit of patients than what the PD-1 alone could achieve as a monotherapy. This combination proposition of course would require a sound scientific and medical data-based foundation, which one hopes Moffitt Cancer Center will present and convey at the Society for the Immunotherapy of Cancer's annual meeting in early-November. Tactically, an effective Keytruda/PV-10 combination with a compelling clinical value proposition should obviate the need for royalty payments to Bristol-Myers/Ono because the '336 combination patent would not be infringed. Increasing anti-PD-1 antibody patent opposition and litigation could tip Merck's decision-making scales in favor of embarking on a near-term combination study of Keytruda and PV-10, with perhaps an eye to a longer-term combination.

Adam Feuerstein: Bristol And Merck's Cancer Drugs Won ASCO. Five Slides Explain Why.

"This isn't a chart of real data but it's the best slide of the ASCO meeting because it explains why cancer immunotherapy is winning over targeted therapies, particularly in melanoma. It's the long survival tail! Targeted therapies work fast but responses tend to be transient as cancer cells develop resistance. This means that early, impressive survival benefit aren't sustainable. Cancer immunotherapy, on the other hand, works slower. It takes time for the patient's immune system to identify and kill cancer cells. But once a patient's T-cells get a taste for cancer cells, their appetite is insatiable. That means tumor responses that are more durable and (hopefully) sustained and prolonged survival."

PV-10 is both a targeted therapy and an immunotherapy.

I Think it's a Good Time to be a $PVCT Shareholder

Shareholders are closer to the end-game for the stock than to their journey's beginning. The company's  life sciences technology is head and shoulders above its peers. The lead compound presents a compelling clinical value proposition capable, perhaps, of indeed shifting the paradigm of cancer treatment (and treatment of inflammatory skin disorders). The drug already is productized, with a product business proposition to match that of the underlying technology. Provectus appears to be nearing transparency regarding regulatory clarity for oncology. The company also appears to be nearing certain license deals that will provide initial market validation. In sum, management, Provectus and its shareholders are nearing the end-game.

Provectus' technology is a game changer, productized to effect the change, and can be delivered and scaled to profit from the change to come.

The technology, PV-10 for oncology, is an effective local treatment capable of as effectively treating distant disease and visceral metastases. The drug, through expression of antigens in context in tumors into which PV-10 is injected fortifies the immune system against cancerous agents. Immunization occurs because PV-10's chemoablation causes rapid, complete, durable necrosis of tumor lesions.

"Scientists have been trying for decades to understand why the body's immune system didn't see cancer cells as the enemy and attack them. Recent discoveries revealed that tumors are adept at cloaking themselves by hijacking the body's own mechanism for preventing the system's T-cells, the infection- and disease-fighting cells of the immune system, from running amok against healthy tissue."

The above quote from Wall Street Journal (WSJ) article New Cancer Drugs Harness Power of Immune System (5/15/13) is not quite on-point. Rather, the quote below from Bloomberg article Human Immune-Boosting Cancer Drugs Seen Extending Lives (5/12/13) is more to the point.

"Now many believe that by strengthening the immune system’s ability to identify and kill cancer cells, they can broaden the attack so it will fight any dangerous malignancy. “You’re setting up a fair fight” with the disease, said Nils Lonberg, a senior vice president at Bristol-Myers, in a telephone interview. “The immune system is just as adaptable as the cancer.”"

How do you strengthen the immune system? Medical science has done it before with infectious diseases. Immune systems can be overwhelmed and, thus, are unable to help the human body fight back. Antibiotics themselves do not cure patients of infectious diseases that have afflicted them. Rather, the immune system cures the hosts with the help of antibiotics. Treating infectious diseases requires that antibiotics should have near absolute specificity for the infectious agent. Tough infections require multiple agents.

I think it's a good time to be a Provectus shareholder.

The volume of the conversations about immunotherapy has grown much, much louder. Take Xconomy's Luke Timmerman's article Genentech Follows Fast at ASCO as Cancer Immunotherapy Picks Up (5/15/13) for example.

"Genentech made its name in cancer by creating targeted antibody drugs that zero in on tumor cells while mostly sparing healthy tissue. Now it’s seeking to compete in the next wave of cancer immunotherapies, which are designed to spark the immune system to attack tumors like a virus."

Or take NBC's Nightly News report Immunotherapy targets cancer cells with remarkable results (5/15/13).

"Cancer cells typically put up a chemical shield to protect against the body’s disease-fighting T cells. But immunotherapy can break down the shield and let the T cells get to work."

The more the biopharmaceuticals industry, investing community and general public talk about immunotherapy, the better the environment or atmosphere for PV-10 and Provectus to flourish.

From the same WSJ article above: "More broadly, Leerink [Swann, a middle market investment bank] believes the "immuno-oncology" drug market could amount to a $20 billion category annually, putting it on a par with the cholesterol-lowering statin market at its height."

From dendritic cells (Dendreon's Provenge) to antitumor antibodies (Bristol-Myers' anti-CTLA-4 agent Yervoy) to immune checkpoint blockades (ASCO 2013's anti-PD1 and anti-PDL-1 agents):

"The immunotherapy of cancer has made significant strides in the past few years due to improved understanding of the underlying principles of tumor biology and immunology...[t]he pillars of human cancer therapy have historically been surgery, radiotherapy, and chemotherapy, but a fourth modality of immunotherapy has been well documented since 1890..." (Kirkwood et al.).

Big Pharma is tacking closer to the ultimate goal, but they mostly still are sailing wide of the objective.

"If the new generation of immune therapies lives up to its promise, “this is going to be a paradigm shift for treating cancer,” said Merck senior vice president Gary Gilliland in an interview. “We are pretty good at shrinking tumors, but not good at getting rid of them. Immune therapy is a way to begin to approach that.”"

Yes, Big Pharma is pretty good at shrinking cancerous tumors, but not yet good enough at making them go away.

Craig's postulation that you treat cancer like you treat an infectious disease requires a/the drug treatment to possess near absolute specificity for diseased tissue (spare normal tissue and clear rapidly from it) and induce a host response (combined apoptosis-autophagy of treated targets because intralesional delivery produces a “vaccine-like” systemic effect that enhances normal human body defenses) over a very wide range of activity (broad spectrum antibiotic-like)


PV-10 chemoablation causes rapid, complete, durable necrosis of tumor lesions.

I think it's a good time to be a Provectus shareholder.

The general discourse at the moment about immunotherapies, however, is far from well understood or a consensus. Take last week's exchange on Adam Feuerstein's Twitter feed @adamfeuerstein below.

Feuerstein had been explaining the fundamental bear case for Vical's Allovectin-7, but aside from perhaps some valid trial design questions, his "red flags" included a lack of positive statements by melanoma experts and institutional healthcare investors as well as a lack of immune-related toxicity by Allovectin-7. Church is not a fan of immune-related toxicity because of the long-term dangers of altering the immune system in order to use it. All of this despite the on-point replies of other respondents: directing T-cells to attack tumors rather than a broad uncontrolled response, the beauty of local treatment is limited toxicity, revolutionary if the local treatment works on visceral mets, etc.

Many monoclonal immunotherapies do cause terrible toxicities, which are related not just related to "taking the brakes off" the immune system. Their target antigens are not only on/in the immune cells they wish to suppress. Just like chemotherapy agents, immunotherapy agents also can cause collateral damage with more adverse side effects like cancer and death.

The nature of the conversation Feuerstein, Church and the others need to have has to be deeper and more substantive. It's too simplistic to say Allovectin-7 does or will not work. Whether it's Allovectin-7 or talimogene laherparepvecone (T-Vec, formerly OncoVEX), or PV-10 itself, one has to balance positive effects with side effects. Think of it as a biological signal-to-noise ratio. One can titer up dosages until one sees bad things happen.

I think Pfizer probably refused to do this with its anti-CTLA-4 agent tremelimumab, which is why it has a greater failure record in clinical trials than it's Bristol-Myers' ipilimumab. Bristol-Myers probably had a higher tolerance for "bad things to happen" in order to suss out the optimal or near-optimal signal-to-noise or benefit-to-side-effect ratio.

Remind yourself of Provectus' combination therapy work at AACR 2013 utilizing PV-10 and a systemic anti-CTLA-4 antibody. The highest dose of the latter killed the murine subjects more quickly. Lower doses were less effective but also less dangerous. Interestingly, the results the company concluded that while PV-10 is highly effective when all existing tumor is accessible for injection, for visceral or other inaccessible disease the combination of PV-10 with CTLA-4 blockade has important potential synergy. Nevertheless, the apparent toxicity at high doses of the anti-CTLA-4 antibody markedly reduced the effect of the antibody alone and the combination of PV-10 and the antibody.

If an immunotherapy is working, there has to be some response (e.g., inflamation, redness, blistering, itching, etc.). These "side effects" come with the territory, and merely are signs the immune system is now in the game. So, while one indeed is generating a toxic response by recruiting the immune system, the key is focusing this toxicity as much as possible.

The problem with Yervoy, and perhaps immunotherapies like anti-PD-1, anti-PDL-1 agents and other treatments, is the collateral damage they cause to the body. PV-10's great strength has been and is its ability to the target only what it kills and kill only what it targets. Another strength is the drug's ability to generate a very specific, targeted, immune response with very little collateral damage to anything but the tumor itself. So, some blistering occurs, body temperature rises, etc. Nothing more.

I think it's a good time to be a Provectus shareholder.

Still, regulatory clarity has to become transparent. Is it an MM Phase 3 trial under SPA powered for for a 6-month progressional free survival for PV-10 vs. 2-month plus PFS for the comparator DTIC?Or is it breakthrough designation therapy and accelerated approval or another accelerated pathway?

Further still, commercial validation through one or more meaningful license transactions (global, regional, dermatology) is required. For example, will it be Hisun-Pfizer Pharmaceuticals in China? Or another company or entity? The Hisun-Pfizer joint venture was established in 2012 to sell off-patent medicines in China and other emerging markets. But economics are economics. Pfizer's 49% equity ownership and thus 49% ownership of any PV-10 sales in China would be a strong inducement to widening the entity's mandate through a license deal with Provectus.

Who will it be in India? In Japan? When will PH-10 be licensed, and to whom?

Provectus is squarely in the eye of key cancer patient advocates. The company participated in Melanoma Research Alliances' (MRA's) Fifth Annual Scientific Retreat in February. In April Peter joined MRA's President and CEO Wendy Selig, LiveSTRONG's President and CEO and Provectus corporate advisory board member Doug Ulman, Moffitt Cancer Research Center's Dr. Shari Pilon-Thomas and some media for dinner.

Key opinion leaders like Moffitt's Dr. Jeff Weber and Dr. Vernon Sondak and Pfizer's Dr. Craig Eagle are enthused about PV-10 as both a monotherapy and combination therapy.

More data is on the way. And data is driving and will drive the deals.

Yes, I think it's a good time to be a Provectus shareholder.

@WSJ New Cancer Drugs Harness Power of Immune System

Full article here.

@Bloomberg @BloombergNews: Human Immune-Boosting Cancer Drugs Seen Extending Lives

An article by Robert Langreth here (May 12, 2013).

"Merck & Co. (MRK), Bristol-Myers Squibb Co. (BMY) and Roche Holding AG (ROG) have opened a new front against cancer with the next generation of experimental drugs that use the human immune system to seek and destroy tumor cells."

"Building on the success of Bristol-Myers’ Yervoy drug for melanoma that reached the market in 2011, drugmakers are devising more potent immune therapies or combining treatments for maximum effectiveness. They are also testing the new medicines in more types of cancers, including lung and breast."

"If the new generation of immune therapies lives up to its promise, “this is going to be a paradigm shift for treating cancer,” said Merck senior vice president Gary Gilliland in an interview. “We are pretty good at shrinking tumors, but not good at getting rid of them. Immune therapy is a way to begin to approach that.”"

"Now many believe that by strengthening the immune system’s ability to identify and kill cancer cells, they can broaden the attack so it will fight any dangerous malignancy. “You’re setting up a fair fight” with the disease, said Nils Lonberg, a senior vice president at Bristol-Myers, in a telephone interview. “The immune system is just as adaptable as the cancer.”"

"Cancer doctors “are accustomed to moving from one therapy to another” as tumors rapidly develop resistance,” he said in a telephone interview. “It is generating tremendous excitement to have a drug class that might well be able to provide long term control of metastatic cancer.”"

$PVCT CEO Letter: PV-10 Compassionate Use Data To Come

When I heard 75% of compassionate use program (CUP) patients were cancer-free (but without any specifics regarding longevity), I wanted context/more information with which to compare this PV-10 success rate. I found some expanded access program data for ipilimumab:

Whether adjusting for patients receiving ipilimumab who were lost to follow-up or not (>20% or more), a "rough" comparison with PV-10 (75%) is notable to say the least.

$PVCT: Bristol-Myers Visits The Blog

Just saying...

(Unlike Daiichi Sankyo, I would not reach too much into Bristol-Myers' visit(s) at this point).

$PVCT: Understanding Why Cancer Vaccines Fail

This article from The Motley Fool is a nice read. The first part of the article revisits an MD Andersen discovery earlier this year that the incomplete Freund's adjuvant, or IFA, a mineral oil-based adjuvant, could be a problem.

The article also highlights other vaccine or vaccine-like treatments like Provenge (Dendreon), Yervoy (Bristol-Myers) and TheraCys (Sanofi), as well as Stimuvax (Oncothyreon) and Allovectin (Vical), ultimately concluding that "[T]he insights from the discovery at MD Anderson will help move cancer immunotherapies further along, but given the long list of failures, it's still a risky area to invest in."

In discussing the impact of these treatments on cancer (tumors), the author misses a critical point; namely, so-called cancer vaccines fail because they are not sufficiently effective directly on tumors in the first place. In other words, these treatments do not kill tumors well enough, while PV-10 does.

$PVCT #AACR2013 Thoughts...

Two summary thoughts from today's release of the AACR abstracts, one by Moffitt and one by Provectus, follow.

Moffitt
The first one derives from the second to last sentence of Moffitt's abstract: "In total, these studies support the induction of tumor-specific T cell-mediated immunity after single treatment with IL-PV-10 in multiple histologic subtypes."

"Multiple histologic subtypes," an extremely comprehensive statement, refers to all cancer indications tested by Moffitt: breast, melanoma, ... Tumor specific immunity was achieved in multiple indications.

Chemoablation via PV-10 ablation causes antigenization, and antigenization causes immunization.

Wachter et al.
The second thought comes from the last sentence of the company's abstract: "The rapid reduction in tumor burden and tumor specific immunologic stimulation provided by PV-10 may complement the immune stimulation of anti-CTLA-4 antibodies such as ipilimumab without increased toxicity."

You will recall I wrote earlier:

The crux of the matter is that PV-10, as a local agent, needs to show systemic potential for life science investors, Big Pharma and the FDA to view the drug as clinically relevant. This is the local agent "burden of proof." There must be systemic potential to be relevant for treating cancer after surgery, where cancer is viewed by definition as a systemic disease. PV-10 is an drug with tremendous local efficacy and before unseen systemic benefit (even more so than systemic agents). 

But PV-10 still is a local agent. 

The mindset of the industry -- medical oncologists and hematologist-oncologists, but not surgeons -- is that a local agent has to be combined with a systemic agent to be relevant.  The industry does not yet realize how much of an impact PV-10 will be just as a local agent. All it can currently understand is that PV-10 works, and harnesses the immune system in novel manner. It is obvious to industry PV-10 will get even better systemic results when combined with other agents, or, other agents will get better results when combined with PV-10.

"PV-10 may complement the immune stimulation of anti-CTLA-4 antibodies...without increased toxicity:" Provectus further elucidates the concept of PV-10 orthogonality to systemic therapies; in this case, systemic immunotherapy in the form of anti-CTLA4 agents like Bristol Myers' ipilimumab (Yervoy) in murine model work. Ipilimumab gets better results when combined with PV-10, with no increased toxicity.

Orthogonality: In geometry, two lines (vectors) are orthogonal if they are perpendicular; that is, they form a right angle. Our three dimensions -- the x-, y- and z-axes -- are orthogonal because each is at right angles with the others: non-overlapping, uncorrelated, or independent of each other. In computer science, orthogonality is "a system design property which guarantees that modifying the technical effect produced by a component of a system neither creates nor propagates side effects to other components of the system." (Source: Wikipedia).

Previously, the company demonstrated orthogonality (in pre-clinical work that led up to the upcoming human trial) with systemic chemotherapy agent sorafenib (in the case of liver cancer/HCC). Sorafenib gets better results when combined with PV-10, with no increased toxicity.

Later, Provectus provided results of orthogonality with [inexpensive] systemic chemotherapy agent 5-fluorouracil ("5-FU") in murine model work. 5-FU gets better results when combined with PV-10, with no increased toxicity.

$PVCT: Provectus to Present Data on PV-10 at the American Association for Cancer Research Annual Meeting in April 2013

Provectus issued a PR yesterday announcing the acceptance of Craig et al.'s poster presentation -- Combination of PV-10 immuno-chemoablation and systemic anti-CTLA-4 antibody therapy in murine models of melanoma -- at the American Association for Cancer Research (AACR) Annual Meeting in April 2013 in Washington, D.C.

Management checked with AACR to see what they could and could not say about the abstract and work in the PR. Provectus, at this point, is allowed to say (i) the abstract is accepted and (ii) the title. They cannot release data until the embargo is lifted, which will be in stages and does not start until sometime in March.

As Craig mentioned during his presentation at the Noble Financial Capital Markets Ninth Annual Equity Conference (click the preceding link to view it) around about minute 14:00, there is very significant interest to see how PV-10 works with systemic treatments (e.g., chemotherapy, immunotherapy, etc.), because it has become clear these secondary treatments work better after an initial use or application of PV-10.

You may recall from my post Provectus Pharmaceuticals Announces H. Lee Moffitt Cancer Center Initiates Phase 1 Study of PV-10 to Elucidate Bystander Effect the notion of PV-10 making cancer treatment more effective in combination with other therapies also is important (very, actually); particularly for late stage patients (a group not targeted by Provectus' current registration pathway for PV-10, which is to facilitate the treatment of Stage III and early-Stage IV patients) and those with heavy tumor burden.

Craig et al.'s work announced today -- the combination of PV-10 and systemic anti-CTLA-4 antibody therapy -- clearly targets and is in response to serious interest from Big Pharma: Bristol-Myers Squibb & ipilimumab/Yervoy and Pfizer/MedImmune-AstraZeneca & tremelimumab (MedImmune in-licensed tremi from Pfizer in 2011 for global development rights to the drug while Pfizer retained rights to specified types of combination therapies).

PV-10 + systemic chemotherapy: Craig etl al.'s murine work -- Generation of an antitumor response and immunity using a small molecule drug (PV-10) -- at the Society for Immunotherapy of Cancer (SITC) 27th Annual Meeting on October 26 and 27, 2012 in North Bethesda, Maryland explored time to progression and tumor growth from PV-10 alone, 2 cycles of 5-FU, PV-10 and 2 cycles of 5-FU, and a saline control. Provectus concluded co-administration of PV-10 immuno-chemoablation with other systemic therapy, in this case, 5-FU, can yield potent synergy in uninjected tumors (Combination of PV-10 with systemic chemotherapy can yield synergistic benefit in untreated tumors supportive of ongoing clinical work; f/n: A study to assess PV-10 chemoablation of cancer of the liver; clinical trial NCT00986661). PV-10 did not interfere with the systemic chemotherapy agent, nor did it create or cause a toxic reaction. In fact, by boosting the immune system, PV-10 allowed the chemo agent to perform better.

PV-10 + radiotherapy: Foote et al.'s initial and ongoing work combining PV-10 and radiotherapy are showing dramatic improvement for patients with much later stage disease (Stage IV) and heavy tumor burden. At least 10 patients have been treated, a follow-up to the success of their initial work on 3 patients.

PV-10 + systemic immunotherapy: As I wrote earlier, there is very significant interest to see how PV-10 works with ipilimumab (an anti-CTLA-4 agent). Because ipi is human-specific, Craig used a mouse anti-CTLA-4 antibody. Craig et al.'s work is a necessary pre-cursor to human trials (one cannot simply run such experiments without sufficient data to show the FDA how the combination might work and that it is safe). This mouse study will be used to convince regulators that Provectus should be allowed to run a Phase 1 trial combining PV-10 and ipi (as Craig mentioned at the Noble conference).

Click to enlarge figure.

Other combinations: As a treatment PV-10 lies in the "sweet spot" of the addressable market of patients afflicted with melanoma that comprises the vast majority of patients. Patients with very late stage disease and/or very heavy tumor burden, depending on whose numbers you use, probably comprises 2-5%. Nevertheless, as with today's announcement that heralds the successful demonstration of PV-10 and a systemic immunotherapeutic agent (as with the company's SITC-presented earlier work that successfully demonstrated the combination of PV-10 and a systemic chemotherapeutic agent) Provectus is seeking further combinations to make very late stage disease patient treatment options better (e.g., intra-tumoral GM-CSF, systemic interleukin, anti-PD-1 antibodies/agents, etc.).

Today's PR is not related to the anticipated Moffitt immunological MOA characterization work (mouse & human) that will be presented later this year at a high profile conference like AACR. Moffitt presumably will notify Provectus if the cancer center's abstract(s) has (have) been accepted. Then, management will work with Moffitt to coordinate news flow.