November 3, 2016

It will take more than just checkpoint inhibition to achieve the next step forward in oncology

Image source
Updated below: 11/3/16 {twice} and 11/5/16.

(alternative blog post title: Can Clever Chronological Combos Cure Cancer?)

Clinicians and medical researchers around the world are growing in their realization that current immuno-oncology is not mission accomplished. It will take more than just checkpoint inhibition to achieve the next step forward in oncology.

Even immunologist Dr. James Allison, PhD, whose work led to the development of anti-CTLA-4 drug ipilimumab (Yervoy), highlighted this "look forward" in Laura Panjwani's October 31st OncLive article entitled "James Allison Says Rational Combinations Key to Immunotherapy Success in "Cold" Tumors:"
"The success of immunotherapies in those cancers—which are likely seeing a better rate of response due to their high mutational burden—is now paving the way for what are known as “cold” tumors, those that don’t have a heavy mutational burden or significant T-cell infiltration. 
There is enough progress being made across the board that I think we can start thinking about some of the colder tumors responding if we just keep studying and making rational combination decisions. As we understand this better, we can rationally put two things together that won’t just duplicate or cancel each other out, but will do different things that can at least be additive, if not synergistic."
Among various combinations of therapies and therapeutics with checkpoint inhibition, Dr. Allison discussed radiation, chemotherapy and targeted therapy in the OncLive article:
"Most of the activity now, at least that I know about, is in radiation...There is also some chemotherapy combination research going on... 
Relatively few targeted therapies are being investigated with immunotherapies, although that research is happening. One of the problems is that there are so many options for combinations; the temptation is there to just combine something from column A, something from column B, and something from column C, and see if it works. That is the way it used to be done back in the empirical days of chemotherapy, but we know enough now to not do that."
PV-10's (Rose Bengal's) clinical & pharmacoeconomic value proposition is clear, simple and straightforward:
Click to enlarge. Sample image source, Sidoti Fall 2016
Germane to this blog post is the value proposition PV-10 provides a combination partner: agnosticism, orthogonality, and synergism:
Click to enlarge. Same sample source as above.
PV-10's combinatorics drug development program/portfolio to date comprises chemotherapy, radiotherapy, and checkpoint inhibition in pancreatic cancer, melanoma, and liver cancer:
  • November 2016, SITC: preclinical (murine models), PV-10 + chemotherapy (gemcitabine/Gemzar®), pancreatic cancer, Moffitt Cancer Center,
  • November 2014, SITC: preclinical (murine models), PV-10 + co-inhibitory blockade [checkpoint inhibition] (anti-CTLA-4, anti-PD-1, anti-PD-L1), melanoma, Moffitt Cancer Center,
  • April 2013, AACR: preclinical (murine models), PV-10 + anti-CTLA-4 [checkpoint inhibition], melanoma, Provectus,
  • November 2012, SITC: preclinical (murine models), PV-10 + chemotherapy (5-fluorouracil/5-FU, Adrucil®), hepatocellular carcinoma (HCC), Provectus, and
* There is not yet sufficient information to suggest patients on a course sorafenib have been treated with PV-10 (see May 10, 2016 1Q16 business update conference call, pp 44-45).

Updated (11/3/16).2: A table of the bullet points above is below.
Click to enlarge
Updated (11/5/16).3: Speaking of old oncology therapeutics and therapies ("In cancer, it’s back to the future as old treatments make cutting-edge ones more effective," Stat, Sharon Begley, August 4th):
"New cancer drugs that unleash the immune system on tumors are all the rage, getting credit for curing former President Jimmy Carter’s advanced melanoma and inspiring tech billionaire Sean Parker to pledge $250 million to cancer research. Behind the excitement, however, is the hard truth that these therapies work in only a minority of patients. 
Now scientists are finding hints of a solution in an unexpected place: Older, out-of-favor cancer treatments such as chemotherapy and radiation may make the cutting-edge immune-based drugs effective against more cancers — even hard-to-treat ovarian and pancreatic tumors... 
One answer: through chemotherapy or radiation. When these old-line treatments begin to kill tumor cells, those cells release molecules that can attract T cells to join in the attack. “They have the potential to prime the pump for immunotherapies,” said Dr. Gary Gilliland, president of the Fred Hutchinson Cancer Research Center in Seattle... 
Radiation, which was first used against cancer at the turn of the 20th century, can also turn cold tumors hot. In a study published in June, scientists led by radiation oncologist Dr. Ralph Weichselbaum of the University of Chicago Medical Center found exactly that in mice with pancreatic cancer, which is notorious for being nearly untreatable, as well as for not attracting tumor-destroying T cells. (The only immunotherapy having any effect on pancreatic cancer in people slowed tumor growth in a mere 8 percent of them.) 
“We think radiation turned a cold tumor into one that attracts T cells, while the immunotherapy kept the T cells from being disabled,” Weichselbaum said. “I think some cancers that aren’t now treated with radiation might be,” as long as immunotherapy follows." {my underlined emphasis} 
Dr. Weichselbaum's paper is here: "Combination of radiotherapy and vaccination overcomes checkpoint blockade resistance," Oncotarget, Zheng et al., June 7, 2016.
The majority of cancer patients respond poorly to either vaccine or checkpoint blockade, and even to the combination of both. They are often resistant to high doses of radiation therapy as well. We examined prognostic markers of immune cell infiltration in pancreatic cancer. Patients with low CD8+ T cell infiltration and high PD-L1 expression (CD8+ TloPD-L1hi) experienced poor outcomes. We developed a mouse tumor fragment model with a trackable model antigen (SIYRYYGL or SIY) to mimic CD8+ TloPD-L1hi cancers. Tumors arising from fragments contained few T cells, even after vaccination. Fragment tumors responded poorly to PD-L1 blockade, SIY vaccination or radiation individually. By contrast, local ionizing radiation coupled with vaccination increased CD8+ T cell infiltration that was associated with upregulation of CXCL10 and CCL5 chemokines in the tumor, but demonstrated modest inhibition of tumor growth. The addition of an anti-PD-L1 antibody enhanced the effector function of tumor-infiltrating T cells, leading to significantly improved tumor regression and increased survival compared to vaccination and radiation. These results indicate that sequential combination of radiation, vaccination and checkpoint blockade converts non-T cell-inflamed cancers to T cell-inflamed cancers, and mediates regression of established pancreatic tumors with an initial CD8+ TloPD-L1hi phenotype. This study has opened a new strategy for shifting “cold” to hot tumors that will respond to immunotherapy."
In Moffitt Cancer Center's upcoming SITC 2016 poster presentation of its PV-10-related work, "Intralesional injection with rose bengal and systemic chemotherapy induces anti-tumor immunity in a murine model of pancreatic cancer," (Provectus press release) (a) Rose Bengal more than likely was administer before chemotherapy (not after, like in Weichselbaum's murine model work of radiation plus checkpoint inhibition), and (b) PV-10 plus chemotherapy induced, elicited, generated, etc. anti-tumor immunity, unlike Weichselbaum's work.

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