January 22, 2016

Combining PV-10 with a Checkpoint Inhibitor Enhances the Systematic Immune Response of PV-10

{Bolded and underlined emphasis below is mine}

2013: In Chen and Mellman's Oncology Meets Immunology: The Cancer-Immunity Cycle [1], cell death is Step #1 (Release of cancer cell antigens [cancer cell death]) below.
Click to enlarge.
Figure 1, The Cancer-Immunity Cycle
Therapies and therapeutics that cause cell death are highlighted in Chen & Mellman's Figure 2 below, again Step #1:
Click to enlarge.
Figure 2, Therapies that Might Affect the Cancer-Immunity Cycle
I think it is well documented in biomedical literature that treatments like chemotherapy, radiation therapy (or radiotherapy), and targeted therapy drugs lead to immunogenic cell death ("ICD").

June 2014: At ASCO, then Senior Member of the H. Lee Moffitt Cancer Center and Director of its Donald A. Adam Comprehensive Melanoma Research Center, and now senior faculty of NYU Langone Medical Center and its Laura and Isaac Perlmutter Cancer Center, Deputy Director of the Perlmutter Cancer Center and Co-director of its Melanoma Program, Dr. Jeffrey Weber, MD, PhD said of clinical PV-10 work undertaken by Moffitt, where patients had metastatic disease refractory to previous ipilimumab, anti PD-1 and/or vemurabenib therapy:
"This data provides more and more evidence that you are altering both local and systemic immunity in a positive way. It also provides a rationale for combination trials of PV-10 with check point protein inhibitors, such as ipilimumab, pembrolizumab and nivolumab. PV-10 might offer the perfect way to prime the immune system." [2]
November 2014: At SITC Moffitt presented their melanoma combination poster entitled Efficacy of Intralesional Injection with PV-10 in Combination with Co-Inhibitory Blockade in a Murine Model of Melanoma; i.e., PV-10 + one of {anti-CTLA4, anti-PD1, anti-PDL1}. I wrote about this in November 18, 2014's blog post Provectus notebook, where the preclinical Moffitt study comprised a single injection of PV-10. Of course, contrast that study approach, which had focused goals, with Provectus' Phase 1b/2 combination therapy clinical development program that sees Stage IV melanoma patients receive injections of PV-10 into all accessible disease (I believe) every 3 weeks for the duration of the study, together with immune checkpoint inhibitor pembrolizumab.

At the time frequent medical writer of PV-10 Janet Fricker wrote article in Medical News Today about Moffitt's SITC 2014 poster presentation entitled Melanoma shows improved regression with combination of PV-10 and checkpoint inhibitor. The article has an interesting quote from the cancer center's Dr. Shari Pilon-Thomas, Ph.D. about their work:
"The spirit of our study was to determine whether combining PV-10 with a checkpoint inhibitor would enhance the systematic immune responses of the initial injection of PV-10."
Phrased via slightly different editing: The spirit of the study was to determine whether combining ABC (PV-10) with XYZ ver 2.0 (e.g., pembro) would enhance the systematic immune responses of ABC (PV-10). Not, whether combining XYZ (pembro) with ABC (PV-10) would help XYZ ver 2.0 (pembro).

January 2016: At the 2016 Genitourinary Cancers Symposium Galsky et al. surmised in Phase II trial of gemcitabine + cisplatin + ipilimumab in patients with metastatic urothelial cancer:
"We hypothesized that chemotherapy may lead to immunogenic cell death, and other immunomodulatory effects, which could subsequently be exploited with the addition of ipilimumab."
Phrased via slightly different editing: Combining DEF (chemotherapy) with XYZ ver 1.0 (e.g., ipi) might enhance/exploit the immune response of DEF.

January/February 2016: At the 2016 Academic Surgical Congress the University of Illinois at Chicago ("UIC") will note:
"Therefore, based on these results, further evaluation of PV-10 as a potential agent to stimulate immunologic cell death in solid tumors is warranted."
  • Immunogenic cell death is critical to the commencement of the cancer immunity cycle.
  • The potency of the initial generation of ICD likely dictates the prolonged or sustained potency of the subsequent cycle steps or cascade.
  • Adding a key combination partner to the mix likely augments the potency and sustainability of the immunity cycle.
  • The greater the synergy between the components of the combination -- the two elements of the pairing -- the greater the potency and sustainability, or durability.
  • Oncolytic viruses, like Amgen's talimogene laherparepvec (Imylgic), also can cause ICD. See, for example, "Oncolytic Virotherapy and Immunogenic Cancer Cell Death: Sharpening the Sword for Improved Cancer Treatment Strategies," Workenhe et al., Molecular Therapy (2014); 22 2, 251–256.
  • Moffitt and UIC, independent of each other, now have shown PV-10 causes potent ICD.
  • Provectus' clinical data from its A Phase 1b/2 Study of PV-10 Intralesional Injection in Combination With Systemic Immune Checkpoint Inhibition for Treatment of Metastatic Melanoma has to be good enough to rise notably above the noise of the many combination therapies trials already being run.

[1] Oncology Meets Immunology: The Cancer-Immunity Cycle, Chen et al., Immunity, Volume 39, Issue 1, 1-10
[2] Provectus outlines path forward for PV-10, Janet Fricker, ecancernews, June 10, 2014

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