Roborant

That is excellent news for Tex, Mike! Thanks for the update. The combo (PV-1+ Pembro) seems to be effective in a much larger set of patients than the Pembro alone (only 20% or so). That's to be expected since the Pembro can only help if one of the problems is that the immune system is being overly downregulated by PD-1 or programmed cell death protein 1 –see https://en.wikipedia.org/wiki/Programmed_cell_death_protein_1). Of course, PV-10 is limited to patients with injectable lesions or tumors, but it can train the immune system to immunize the body against any cells that share the same mutant antigens (cell markers) with those that it has been injected into.

The big problem is, of course, that the cancer patient’s immune system is not identifying that the cancer cells are enemy cells and thus does not attempt to destroy them (otherwise, . Only those cancers cells that are able to cloak themselves or evade the immune system in some way can survive in a patient with a normal immune system that is not being down-regulated by one of the body’s various immune system checkpoint mechanisms (that serve to prevent auto-immune disorders when normal cells come under immune system attack).

PV-10’s MOA (method of action) studies performed by Moffitt Cancer Center researchers find that PV-10 molecules invade the cell walls of cancer cells because of the unique properties of PV-10 and the acidic micro-environment of cancer cells. Normal cells are unaffected. Once inside the cancer cells, the cell begins to “lyse” and the cell bursts open.

Many other injectable substances can kill cancer cells but PV-10 is unique in 2 important ways.

One, it is safe and non-toxic to normal cells and has a half-life of about 30 minutes (except that portion which has entered the walls of cancer cells). It is excreted into the bile by the liver.

Two, after lysis, where the cell walls have burst open, killing the cancer cell, the cancer cell neoantigens (which may have been hidden previously) are preserved intact and not denatured as they are by other cancer killing agents (which are generally unsafe for normal cells.) This allows the immune system to produce specific antibodies for any newly discovered antigens thereby creating a vaccine effect for any additional cells with an identical neoantigen.

I am using the term neoantigen for antigens that are “new” that is, they are unique to cancer cells and not present in normal cells which have antigens that are known to the immune system as being “self”-antigens – those markers that allow a cell to prove it’s not an invader or a mutant. Neoantigens are those antigens that are not on the “safe” or “self” list.

Cancer cells, by definition, are mutated and over time they continue to mutate and thus the neoantigens by which the body identifies them can change as well. The more unique mutated cancer cells that are lysed and release intact their neoantigens, the better the chance that all of the various mutations of cancer cells can be detected and attacked.

This is why current PV-10 protocols allow for treating and retreating lesions until there are none that can be injected. The idea is both to reduce the tumor burden directly and attempt to release as many of the neoantigens (cancer markers that can be used by T-cells) as possible so that all of the many cancer cell mutations can be identified and killed by the immune system. It’s a Darwinian scenario for the cancer cells. By definition, only those that survive can multiply (and potentially continue to mutate). The purpose of Pembro at this point is to allow the immune system to be more aggressive (literally uninhibited), making more likely that cancers cells with the now-known neoantigens will be targeted and killed. The doctors must monitor side effects so they can limit the cytokine storms that can result from Pembro and other checkpoint inhibitors.

As to question 3, A trial at MD Anderson with low side effect profile has added a 10 slot cohort for Uveal melanoma with hepatic (liver) metastases.  Recent NED patient there, inspiring forum poster, TexMelanomex, used the same drug  (along with Pembro) starting last fall and is now NED for stage IV Melanoma (read his posts if you haven't already). Most cancer trials result in many AE's caused by the treatment and are ultimately not successful. This paticular drug is unique in its method of action and it directly lyses injected lesions and appears to arm the immune system by releasing the un-denatured antigens (the markers of the mutations) so that T-cells can be trained to find other traces of cancer with the same antigens. This mimics normal immune responses (when they are successful).  Best wishes to you and your Father in Law.

Tex, 

Is the trial you were in still available? I think I remember that you were the last of 24 availble in the phase 1b.  https://clinicaltrials.gov/ct2/show/NCT02557321 says Phase 2 will have room for another 120 patients, but this time it's 50 % Keytruda alone and 50% combination of Keytruda and intralesional PV-10. No word on when that actually becomes available. Your success bodes well that more patients will get a shot at this combination soon.Congratulations on your latest NED report. 

Happyfeet, For the moment it appears that the PV-10 monotherapy trial is available in California only in San Diego. MD Anderson is one of the other 20+ actively recruiting sites.My friend's wife commuted to MD Anderson from North Alabama for many years. Unfortunately,she missed out on imunnotherapies like pv-10 and the checkpoint inhibotors before she finally succumbed to melanoma 5 years ago at 42. My friend was fortunate  enough to obtain temporary duty for NASA in Houston for awhile to facilitate her treatment at MDA. Hope you find the best treatment for you.

Always uplifting to read stories of the warriors here having success fighting back and winning battles against melanoma.

Coincidentally, here is a trial found on clinical trials.gov featuring both of those two intralesional therapies you mentioned as helpful to in-transit melanoma (PV-10 vs T-VEC) arms in competition in a phase 3. The TVEC arm is Dr.’s choice of TVEC or chemo. 

PV-10 vs chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma

ClinicalTrials.gov Identifier: NCT02288897
Recruitment Status : Recruiting
Last Update Posted : April 20, 2018
See Contacts and Locations (25 locations)

Sites include your cancer center in Florida Moffitt with Dr Jonathan Zager and MD Anderson with Dr Merrick Ross where TexMelanomex was treated (but in a different pv-10 trial). I see several notable Melanoma KOLs running sites. 

Sanjiv Agarwala at St Luke’s in PA

Robert Andtbacka at Huntsman in UT

Axel Hauschild in Kiel Germany. 

These last two were intralesional therapy skeptics before they were convinced otherwise by good data. 

I hope everyone here has tried to survey clinicaltrials.gov periodically to keep up with new trials or sites that are now recruiting for patients to discuss with their doctors.