September 5, 2015


[In no particular (including chronological) order:]

September 2, 2015 / The undifferentiation of immune checkpoint inhibitors? Incyte Corporation (Nasdaq: INCY), a nearly $21 billion biopharmaceutical company as of a 9/4/15 share price close, announced a global license and collaboration agreement with China's Jiangsu Hengrui Medicine to develop and commercialize the latter's investigational anti-PD-1 agent (SHR-1210). Under the agreement, Incyte would have exclusive worldwide rights to SHR-1210 except for mainland China, Hong Kong, Macau and Taiwan.

Possible or potential item takeaway: For the deal structured and money paid by Incyte, it didn't want or couldn't get from Jiangsu Hengrui Medicine China and SARs.

According to the Incyte press release "SHR-1210 is expected to enter proof-of-concept studies for the treatment of patients with advanced solid tumors in the coming months." {Italicized emphasis is mine}

As backdrop, as FierceBiotech's John Carroll writes, "[a] little more than a year ago Incyte swiftly lined up combination deals that matched its IDO1 inhibitor, epacadostat (INCB24360), with PD-1 and PD-L1 drugs from Bristol-Myers Squibb ($BMY), Merck ($MRK), Roche ($RHHBY) and AstraZeneca ($AZN). INCB24360 is an immunotherapy designed to amp up an immune system attack on cancer, while the checkpoint programs are designed to dismantle cancer cells' cloaking mechanism that prevents an assault from happening." The idea of the combination therapy approach above is/was the use of an immune system amper upper — Incyte's IDO1 inhibitor epacadostat (INCB24360) — to help/assist/partner with the back-end — immune checkpoint inhibitors or co-inhibitory blockade agents like anti-PD-1 and anti-PD-L1 agents from the above mentioned companies.

Last year, for example, Roche partnered up with NewLink and its IDO inhibitor (NLG919). Later, in 2015, Roche partnered with India's Curadev Pharma and its IDO inhibitor.

According to Chen and Mellman's 2010's Oncology Meets Immunology: The Cancer-Immunity Cycle, IDO inhibitors do not appear to be front-ends or immune system accelerators or amper uppers or stimulatory factors or agonists or co-stims but rather back-ends or inhibitors or antagonists.
Click to enlarge. Image source (Figure 2)
Possible or potential item takeaway: Incyte brought an immune checkpoint inhibitor in-house because...
  • Combination therapies [of some sort] will become standard of care for advanced-stage cancer (eschewing [making obsolete] monotherapeutic use of immune checkpoint inhibitors)?
  • It is better to own both parts of the pairing for various clinical and/or business reasons?
  • If it is better to own both parts, differentiation of co-inhibitory blockade is more business (or marketing) than clinical?
  • Win or lose, Bristol-Myers PD-1-related lawsuit against Merck is irrelevant (or its outcome de minimis)? "Every" biopharmaceutical company, including Chinese companies for their own domestic (as well as for international collaboration purposes), has or will have an immune checkpoint inhibitor?
September 1 / A new class of immunotherapy.
Image source
If/when PV-10 stands on the cusp of approval (in T-Vec's case, while not certain, probable approval would occur by or before the drug's October 27, 2015 PDUFA date), it would be a new class of immunotherapy. And St. Luke’s University Health Network's Dr. Sanjiv Agarwala would be PV-10's Dr. Howard Kaufman, MD. See Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part I (July 13, 2015) on the blog's Current News page.

Possible or potential item takeaway: What is PV-10? An ablative immunotherapy? An autologous vaccine? An oncolytic immunotherapy? PV-10 has no specific target, receptor or pathway; however, this item cannot be properly discussed at the current time because knowledge and discussion presumably definitively relies on the presentation/publications of the results of Moffitt Cancer Center's mechanism(s) of action study due later this year. See August 29, 2015 blog post PV-10 has much better gas mileage.

September 1, 3 and 4, 2015 / Tinkering with Mother Nature. The official blog of AACR posted a 9/1 entry by Dr. Srivani Ravoori, PhD entitled Advances in Immunotherapy: Fine-tuning CAR T Cells. On 9/3 FierceBiotech's Carroll wrote an article entitled Novartis team tracks remissions of 4-plus years in a pioneering CAR-T study. In The Pipeline's Dr. Derek Lowe, PhD blogged CAR-T Follow Up on 9/4.

Ravoori wrote about scientists from the University of Pennsylvania and The University of Texas MD Anderson Cancer Center tinkering with the target-binding end of CAR T cells to make them safe for patients with solid tumors:
"CAR T cells designed to target CD19 in B-cell cancers are not selective. They cannot distinguish cancerous B cells that have high levels of CD19 from normal B cells that have physiological (lower) levels of the same protein. But this does not severely impede treating B-cell malignancies because a patient’s immune system can function even when normal B cells are depleted. This form of immunotherapy, however, is not readily adaptable to solid tumors because targetable proteins present on the cancer cells of solid tumors, such as ErbB2 and EGFR, are also present on normal cells that form the vital organs of the body. While losing normal B cells when treated with CD19 CAR T-cell therapy poses manageable side effects in a patient, loss of normal cells that are part of vital organs when treating solid tumors with CAR T-cell therapy can damage these vital organs, which has serious consequences. In fact, in a case report, CAR T cells designed to target ErbB2 present in metastatic colon cancer cells also attacked cells in the patient’s lungs that had low levels of ErbB2, resulting in severe toxicity and death. So, it became evident that if CAR T-cell therapy were to work for solid tumors, engineering T cells that can selectively target cancer cells and spare normal cells is inevitable." {Underlined emphasis is mine}
But, according to Ravoori:
Enter scientists from the University of Pennsylvania and The University of Texas MD Anderson Cancer Center, two teams that used different approaches to answer the same question: Will lowering the affinity of CAR T cells to the target protein make them selective to cancer cells that have high levels of the protein and spare normal cells that have low levels of the same protein? Based on the data the two teams published independently in the AACR’s journal Cancer Research, it appears the answer is “Yes.”
Carroll wrote:
Five years after the University of Pennsylvania began recruiting a small group of 14 patients with hard-to-treat chronic lymphocytic leukemia, researchers are still tracking three of them who are still alive with no signs of their cancer returning after being treated with a first-generation CAR-T therapy...Out of the 14, four experienced complete remissions, meaning their cancer was no longer detectable. One of those four later died of other causes. Four patients had partial responses, with two of them dying after 10 months and 27 months of therapy. One of the partial-response patients died from a pulmonary embolism, and the other was switched to a different therapy after 13 months and died after three years.
But, according to Carroll:
All of the patients who responded to the therapy experienced a potentially life-threatening case of cytokine release syndrome, sometimes called a cytokine storm, with the drug triggering high fevers and in several cases difficulty with breathing and low blood pressure. Doctors responded with the antibody drug tocilizumab and steroids, and all of the patients survived...In a small study like this, investigators can learn as much from failure as they can from success. Testing the 6 patients who did not respond, the scientists said that their customized T cell populations did not expand as aggressively as in the patients who were first flattened by a cytokine storm in their first response to the solo treatment. 
Finally, Lower wrote (about the Novartis study):
"So there’s definitely something major here, and definitely room to improve it. That’s what Novartis, and Juno, and Kite (and who knows who else) are frantically working to do right now. The biggest prizes are to extend this idea to more tumor classes, and to make it scalable to larger numbers of patients. The second one is a big challenge, and the first is even bigger. People have been antigen-hunting for quite a while now, looking for something that’s fit to turn the immune system on in other types of tumors, and it’s slow going. But you have to be sure, because if the immune system can strip a couple of pounds of aberrant white blood cells out of your system, so vigorously that it nearly overloads your kidneys, then it can do the same with lots of other tissues, too, some of which you might prefer to keep. Ripping out a couple of pounds of motor neurons or Kupffer cells would be suboptimal, to say the least."
Possible or potential item takeaway: Safety, specificity, durability? Questions UPenn/Novartis and MD Anderson are a long, long way from fully answering.

September 4, 2015 / A Rumsfeldian Perspective. Lowe, in his 9/4 blog post, wrote "People have been antigen-hunting for quite a while now, looking for something that’s fit to turn the immune system on in other types of tumors, and it’s slow going."

US Secretary of Defense Donald Rumsfeld was once quoted as saying"...because as we know, there are known knowns; there are things we know we know. We also know there are known unknowns; that is to say we know there are some things we do not know. But there are also unknown unknowns – the ones we don't know we don't know."

As Provectus' Chairman and CEO Dr. Craig Dees, PhD has discussed with me almost from the beginning of my due diligence and share ownership (paraphrasing in Rumsfeldian), there antigens we know, antigens we don't know, and antigens we don't know we don't know.

And this knowledge or lack of knowledge (crucially relevant in the treatment of cancer because antigens equal targets) is but one aspect of Dees, President Dr. Tim Scott, PhD and CTO Dr. Eric Wachter's belief that killing cancer tumors in the correct way held the key to successful medical treatment because a proper approach could enable the immune system to stimulate cancer-killing cells throughout the body.

Properly destroying cancer tumors means killing only tumors and doing so completely, quickly and, very importantly, safely (that is, leaving healthy tissue unharmed). They believe this approach is the only effective way of sustainably stimulating a person’s natural anti-cancer defenses. Instead of bathing the entire body or even parts of it with radiation, or filling the bloodstream with oral or intravenous chemotherapies or present-day immunotherapies, Dees et al. firmly hold the position that stimulating the immune system is best achieved through treating tumor tissue by injecting into it a drug capable of destroying the entire tumor as quickly as possible without damaging surrounding healthy cells. Completely also means everything from visible tumor tissue to occult or hidden cells in and immediately around the injection site. Quickly means having the drug processed through and excreted from the body in short order. Antigens generated from the tumor destruction caused by drug injection then can be presented to the body’s cells responsible for selecting the best and most relevant antigens in order to encourage cancer-killing cells to replicate themselves throughout the body. Importantly, tumor antigens have to be viewed in context; physical tumor destruction techniques such as heating or freezing tissue destroyed fragile antigens and disrupted their relevant contextual structures. Disruption of cell membranes and removal of lipids, proteins, and complex carbohydrates destroy the antigens’ context, which is to what immune system cells respond. Thermal destruction denatures potential antigens, changing their chemical structure so that they were no longer representative of the tumor cell. In order to work rapid destruction of tumors has to preserve both antigenic structure and biological context. (Paragraph source, with slight edits by me for verb tense: MicroCap Review, pp. 6-8, September 2015)

Possible or potential item takeaway: For Craig et al. to have PV-10, and themselves, more fully recognized, all constituents of the biopharmaceutical ecosystem are going to have to embrace the above.

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