May 3, 2016

Catching On

Updated below.

Takeaways and a Question:
  • Getting T cells into cancer tumors is important to more successfully fighting the disease.
  • Traditional cancer treatments do not kill enough cancer cells. Immunotherapies like immune checkpoint inhibitors kill more cells than traditional treatments, but they still do not kill enough.
  • Ways of getting T cells into tumors include chemotherapy, radiotherapy, targeted therapies and intralesional (IL) or intratumoral (IT) agents like Amgen's talimogene laherparepvec (T-Vec) (Imylgic®) [approved as a single agent], Provectus' PV-10 [in a pivotal Phase 3 trial as a single agent], Viralytics' Cavatak (another oncolytic virus) [having done Phase 2 trial work as a single agent], etc.
  • The more (quantity) and better (quality) T cells that get into cancer tumors, the greater the immunologic signalling of the drug or drug compound (immunotherapy) that led to said infiltration.
  • If a drug or drug compound's immunologic signalling is so powerful and broad as to enable the Cancer Immunity Cycle to cycle more sustainably and durably, what would have come first, the chicken or the egg (i.e., the left-hand side, or the right-hand side, the antigen cascader or the checkpoint inhibitor)?
Big Pharma-oriented blogger and publisher, and industry consultant, Dr. Sally Church, MD recently wrote a post (on her blog Biotech Strategy Blog; subscription required) asking if chemotherapy was immunotherapy: "Controversy: Is Chemotherapy Immunotherapy?" Her thoughts derived, in part or in whole, from her visit to AACR 2016. She noted in this post (alluding to a prior one) that one of the rate limiting steps in the Cancer Immunity Cycle was "getting more T cells into the tumours so that subsequent immunotherapy can be even more effective." One way to get more T cells into tumors, according to Dr. Church, was chemotherapy.
Click to enlarge. Tweet image source
Getting T cells into cancer tumors, from the perspective of a traditional treatment like chemotherapy, begins with generating antigens caused by killing cancer cells.
Click to enlarge. Figure 3, Chen and Mellman. Immunity 2013; 39: 1-10.
Utilizing therapeutics or therapies (immunotherapies) from the left-hand side of the Cycle to facilitate the infiltration of presumably educated and trained T cells into cancer tumors, therapeutics (immunotherapies) from the right-hand side can be, to use Dr. Church's words "even more effective."

Following Dr. Church's writing, primarily her tweets (and related or associated material) on Twitter (@maverickNY), is necessary for this investment project. She was kind enough to answer some basic questions of mine early on in my due diligence (basic for her, not so basic for me at the time). With 20 years of experience in the pharmaceutical industry that included the development and launch of Gleevec by Novartis (bios here and here), Dr. Church is smart, intelligent, thoughtful, and (I believe) a weather vane of Big Pharma's market/marketing (and, possibly, R&D) interest and direction. For example, she was and presumably remains a fan of checkpoint inhibitors, but has evolved her views (as I believe them to have developed) in regards to treating late-stage disease from such agents strictly as stand-alone, single agent therapies to their greater relevance and effectiveness in combination with other therapeutics and therapies (presumably stimulatory ones complementary to these inhibitory agents).

AACR 2016 not only discussed chemotherapy as a "potential immunotherapy" (viewing this through Dr. Church's prism), the conference also considered and contemplated radiation therapy or radiotherapy — but fractionated treatment, where radiation treatment is given in several, small doses over a period of time. This is about killing cancer cells to begin the antigen cascade (immunogenic cell death). This is about harnessing the cancer patient's tumor(s) to become a vaccine, so to speak (in situ vaccination).

PV-10 + Chemotherapy. Ironically, as an aside, at SITC 2012 (October), three-and-a-half years before AACR 2016 (April), Provectus presented the results of murine model work combining PV-10 and chemotherapy that generated the best response in non-injected (untreated) tumors {underlined emphasis below is mine}:
"The mechanism by which PV-10's bystander effect is produced was investigated using hepatocellular carcinoma (HCC) and melanoma tumors in immunocompetent and immunodeficient mice. In one set of experiments using immunocompetent mice with bilateral HCC tumors (i.e., two HCC tumors in opposite flanks), intralesional injection of PV-10 into one of the two tumors led not only to eradication of the injected tumor, but also to regression of the uninjected tumor. Controls treated with saline exhibited no effect in either tumor. Treatment of mice with systemic chemotherapy (i.e., 5-fluorouracil, "5-FU") had minimal effect on either tumor, while combination of intralesional PV-10 with systemic 5-FU elicited maximal response in uninjected tumors. Data were analyzed by tumor (i.e., injected tumor, uninjected tumor and total tumor burden) for time to progression and for tumor growth. PV-10 alone was favorable to saline control in all categories, while PV-10 combination therapy produced highly significant advantage vs. control for time to progression of treated tumors (p = 0.010), untreated tumors (p = 0.011) and total tumor burden (p = 0.004)." (Source: Provectus press release, October 2012)
Click to enlarge. Image source
Click to enlarge. Image source
PV-10 + Radiation. Even more ironic, and as a further aside, Provectus shareholders await the presentation or publication of an investigator-initiated study in Australia combining PV-10 and radiotherapy in patients with advanced melanoma. You know...what the company's CTO Dr. Eric Wachter, PhD said more than a year ago in response to a question of mine.

As background, Radiation therapy has been combined with PV-10 in two situations. First, in 2010, Foote et al. reported on their combination work on 3 patients in A novel treatment for metastatic melanoma with intralesional rose bengal and radiotherapy: a case seriesMelanoma Research, 20:48, Jan 2010. All of the patients originally were enrolled in Provectus' metastatic melanoma Phase 2 trial (I believe). All patients achieved complete response (CR) (note detailed descriptions in the article's text); however, no discussion was provided regarding survival (that is, keep in the mind the difference or differentiation between [objective] response rate and overall survival). Note: PV-10 was administered firstfollowed by radiation.
Click to enlarge. Fuzzy purple underlined emphasis is mine.
Later, in 2013, Tan and Neuhaus reported on their combination work on 2 patients in Novel use of Rose Bengal (PV-10) in two cases of refractory scalp sarcomaANZ Journal of Surgery, 83:1-2:93, Jan 2013. Both patients were treated in the company's compassionate use/expanded access program (I believe). One patient achieved a complete response, while the other enjoyed "good" clinical effect before progressing again. Also, no discussion was provided regarding survival of the patient achieving CR. Note: Here, radiation was administered firstfollowed by PV-10.

During the 4Q15/CY 2014 business update conference call on March 11, 2015, I asked about the timing, and possibly the potential venue(s) (medical conference, journal), of Foote et al.'s clinical follow-up work combining PV-10 and radiotherapy? Eric said: "But regarding the radiation therapy publication by Foote, that is of record as having led to an investigator-initiated study that you mentioned, 25 patients. That study has been enrolling slowly. It had very specific eligibility criteria at a single center. We have had discussions over the last several months with the investigator about ways to get data from that study available publicly and we anticipate that sometime in the coming months, that is sometime this year, that there will be some presentation of interim data from that study" {my underlined emphasis; this year = 2015}.

Step #5, Infiltration of T cells into Tumors. PV-10 has been potentially implicated in each and every step of the Cancer Immunity Cycle, with data on Step #5 to come.
Click to enlarge. Image source
Click to enlarge. Image source
If PV-10/Rose Bengal can (has) overcome one of the Cancer Immunity Cycle's rate limiting steps (of getting T cells into cancer tumors) in greater quantity and better quality (than other treatments), would Dr. Church then refer to PV-10 as immunotherapy?

Updated (5/20/16): Dr. Church updated or extended her thinking with one of her Blue Ice Publishing episodes at Novel Targets entitled Episode 12: Of Mice and Men. In it she further expands on chemotherapy as immunotherapy, and potentially a partner for other immunomodulatory agents like checkpoint inhibitors.
Click to enlarge. Tweet image source

Inception to date: PV-10 + [something else]
Click to enlarge.

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