September 21, 2014

Co-stimulatory & Co-inhibitory

Moffitt's PV-10 presentation at the 2014 annual meeting of the Society for Immunotherapy of Cancer ("SITC") is entitled Efficacy of intralesional injection with PV-10 in combination with co-inhibitory blockade in a murine model of melanoma (see Moffitt @ SITC (September 19, 2014) on the blog's News page).

Earlier this month, one of the SITC presentation's co-authors and Moffitt assistant professor and researcher, Dr. Shari Pilon-Thomas, Ph.D., co-authored an online OncLive article entitled Immunotherapy Combined With Chemotherapy for Pancreatic Cancer: A Game Changer? (see blog post Treating Cancer). In it Dr. Pilon-Thomas and her fellow authors write:
Of note, the immune system’s involvement in cancer development and progression has sparked much interest in recent years. The model of the cancer-immunity cycle suggests an interplay of immune-suppression and immune-stimulation. In normal individuals, a state of immunosurveillance is in place. However, within the tumor microenvironment, inhibitory signals and immunosuppressive cells are present and tip the scale in favor of immune suppression. {Underlined emphasis is mine}
Continued: The idea of the cancer-immunity cycle proposes that, for a cancer immune response to be generated, the net balance between immune stimulation versus immune suppression must be tipped in favor of the former. Studies in various cancers have suggested that tumors evade the immunogenic process mostly by factors that promote immunosuppression. {Underlined emphasis is mine}
The theory of immune surveillance suggests, according to Peggs et al., "...that the immune system plays a key role in suppressing tumor growth and that the incidence of cancer would be much greater were it not for the ability of the immune system to identify and eliminate nascent tumor cells...While the immune system appears capable of eliminating or containing early tumor growth, some tumor cells escape detection and eventually cause cancer." Said another way, when thinking about the growing potential role and promise of cancer immunotherapy, "...we continually develop malignant cells every day that are consumed by the immune system to prevent tumor development, and the immunotherapy drugs seem to target the failure of immune recognition and immune response" (Dr. Peter Salgo, M.D.).

The balance between co-stimulation and co-inhibition is described by Inman et al.: "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."

So, it would seem to me, generalizing (or simplifying, perhaps too much):
  • If co-stimulation > co-inhibition, the immune system can act decisively against cancer,
  • If co-inhibition > co-stimulation, cancer overwhelms the immune system and renders it ineffective or useless, and
  • If co-stimulation = co-inhibition (that is, some sort of equilibrium state), the immune system wages battles against cancer to varying degrees of success with potentially no ultimate resolution to the war itself.
[Daniel] Chen & Mellman (2013), authors of Oncology Meets Immunology: The Cancer-Immunity Cycle, note stimulatory and inhibitory factors at step of the cycle.
Click to enlarge. Figure 2 (above) of [Daniel] Chen et al.'s article.
The authors write:
Each step of the Cancer-Immunity Cycle requires the coordination of numerous factors, both stimulatory and inhibitory in nature. Stimulatory factors shown in green promote immunity, whereas inhibitors shown in red help keep the process in check and reduce immune activity and/or prevent autoimmunity.
[Daniel] Chen et al. then note "[t]he numerous factors that come into play in the Cancer-Immunity Cycle provide a wide range of potential therapeutic targets."
Figure 3 (below) "...highlights examples of some of the therapies currently under preclinical or clinical evaluation. Key highlights include that vaccines can primarily promote cycle step 2, anti-CTLA4 can primarily promote cycle step 3, and anti-PD-L1 or anti-PD-1 antibodies can primarily promote cycle step 7. Although not developed as immunotherapies, chemotherapy, radiation therapy, and targeted therapies can primarily promote cycle step 1, and inhibitors of VEGF can potentially promote T cell infiltration into tumors—cycle step 5."
Click to enlarge. Figure 3 (above) of [Daniel] Chen et al.'s article.
In my illustration below, found on the blog's PV-10, and the Cancer Immunity Cycle, I endeavored to show Provectus' drug promoted steps 1, 2, 3 and 7. I believe, but with no confirmation of course, Moffitt has shown via primarily their murine model work (and maybe their human study) that PV-10 promotes steps 4, 5 and 6.
Click to enlarge.
I revised my table of combination study deals to reflect [as I think they are] stimulatory and inhibitory compounds is below.
Click to enlarge.
Pilon-Thomas et al. concluded (note the article discussed immunosurveillance in the context of chemotherapy, immunotherapy and pancreatic cancer):
The cancer-immunity cycle is an ideal model to envision how tumor cells evade immuno-surveillance as well as where future modalities may intervene with hopes of potentiating tumor cell death. The cancer-immunity cycle together with the immune-modulating functions of chemotherapies that are used in pancreatic cancer creates a rationale for investigating vaccine-chemotherapy combinations. 
Studies to date have suggested benefits of adding immunotherapies to standard chemotherapy regimens. Additional benefits are also suggested by the indication that immunotherapy may render improved chemosensitivity at later dates. In addition, vaccines are often well tolerated with minimal toxicities, which make them a favorable approach. The hope is that we can identify the appropriate combination of vaccine and immune-modulating chemotherapy that will eradicate the disease. There is also likely to be a role for immune checkpoint therapy with inhibitors of PD-1 and PD-L1. Such phase I single-agent studies are currently in progress for pancreatic cancer. The results of studies so far create hope that the combination of chemotherapy with immunotherapy may be a game changer in the treatment of pancreatic cancer.
PV-10 has some interesting features that cross categories. Provectus management previously had called the drug as a chemoablative immunotherapeutic agent (later revising the descriptor to "immuno-chemoablative"). Underlined portion number one, "chemoablative," described PV-10's chemotherapeutic-like feature of rapid tumor ablation and destruction mechanism of action ("MOA"). Underlined portion number two, immuno," described the drug's MOA whereby it harnessed the immune system to battle cancer locally (at the site of injection) and elsewhere around the body.

While not specifically a vaccine because PV-10 is not antigen-specific, it could be considered vaccine-like because it is minimally or not at all toxic but expresses many, many more than one antigen.

As a side note, immune checkpoint therapy in the above Moffitt comments refers to, I believe, ipilimumab, which is why anti-CTLA4 is in step 3, priming and activation, of the cancer immunity cycle (and why Bristol-Myers is exploring the combination of ipilimumab and anti-PD-1 agent nivolumab.

[Lieping] Chen et al. write, when discussion combination therapies:
Traditional chemotherapy and radiation therapy, together with depleting mAbs or treatment with small-molecule inhibitors, all directly target and kill cancer cells, leading to the destruction of the tumour stroma and the release of tumour antigens. When coupled with these direct killing mechanisms, immunomodulatory biologics promote the priming and expansion of existing tumour-specific T cells and their de novo generation, with a potential to form long-lasting and self-sustained antitumour responses. In recent years, small-molecule inhibitors targeting tumours that harbour mutated BRAF (vemurafenib (Zelboraf; Plexxikon/Roche)) or translocated BCR–ABL (imatinib (Gleevec; Novartis)) have shown high initial response rates in clinical trials165. However, the duration of the antitumour response is limited owing to acquired drug resistance. A combination of these fast-acting small-molecule inhibitors with immune co-inhibitory blockade — for example, with CTLA4-specific or PD1-specific mAbs — could promote the priming and expansion of tumour-specific CTLs against multiple tumour antigens and/or epitopes, prevent the generation of escape variants or drug-resistant mutant cancer cells and induce sustained T cell responses. {Underlined emphasis is mine.}
Circling back to beginning of this post, Moffitt's presumed presentation at SITC potentially entitled Efficacy of intralesional injection with PV-10 in combination with co-inhibitory blockade in a murine model of melanoma, the cancer center previously have described their successful pre-clinical work that combined PV-10 with systemic immunotherapies to mean, I believe, checkpoint inhibitors (e.g., ASCO 2014).

The interplay of co-stimulation and co-inhibition (with the goal of more of the former than the latter), and Moffitt's use of what seems to be the broader term co-inhibitory blockade, I wonder whether their work describes the better therapeutic outcome of PV-10 and inhibitory factors of step 7 of the cancer immunity cycle above (see Figures 2 and 3 of [Daniel] Chen et al.).

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