"So my hope is that we can engineer CAR T cells with sufficient machinery to “rescue” CAR T technology from the reality of an antigen-poor landscape. The technology is stunning, but I wonder if in the face of such challenges one ought not to look around, and perhaps take another approach. As it turns out, nearly all cellular therapy companies that have taken on the CAR T field have begun to diversify - we’ve been asking what problems we are solving with these clever twists on the basic technology – and this is well worth pursuing. However in the face of a limited pool of targets, lets perhaps consider a technology with a much much larger target list: tumor neoantigens as recognized by T Cell Receptors (TCR). TCR and TIL technologies offer some interesting solutions, and their own unique challenges…" {Underlined emphasis is mine}Rennert highlights several well known problems of the CAR T field, the below taken verbatim from his post:
- CAR T cells must be highly selective for the target cancer to avoid unwanted killing of other cells, tissues, organs
- CAR T cells must proliferate and persist once injected into the patient (i.e. in vivo)
- Since most CAR T technologies are based on a personalized medicine approach – your cancer attacked by your engineered T cells – there is a fair amount of cell culture to do between harvesting your T cells, altering them (via retroviral or other cell transduction technique), expanding those altered T cells so there are enough to “take” upon injection back into the patient. All of this is expensive, with a typical guess at the price tag of 500K USD
- CAR T therapy is dangerous (although a bit like Formula One racing – very dangerous and just barely controlled). The danger comes from the potential for off-tumor cell killing but also from tumor lysis syndrome, which happens when large numbers of tumor cells are suddenly killed – all sorts of cellular signals get released and this causes an intense and systemic physiological breakdown – very dangerous, but controllable in an appropriate intensive care unit (so recovery care is also very expensive)
- CAR T therapy to date has had limited success outside of refractory acute lymphocytic leukemia (ALL). Now, while refractory ALL is a poster child of an indication – intensely difficult to treat, with many pediatric patients – there are about 4000 such patients in the US each year. Commercially, this is limiting.
- Cancer-specific targets suitable for CAR T technology are very rare.
His list of CAR T technology/company problems are a perfect foil for PV-10 and its own solutions. I believe a new narrative about PV-10 goes something like this: A compound that both agnostically ablates tumors and perfectly primes the immune system. Being copiously liberal with Rennert's list, consider the following below about PV-10.
A. Highly selective
F. No specific target, receptor or pathway
This item cannot be properly discussed at the current time because knowledge and discussion relies on the presentation/publications of the results of Moffitt Cancer Center's mechanism(s) of action study due later this year.
- Provectus: PV-10 itself exhibits antitumoral activity targeted only on diseased tissue while sparring normal tissue (SITC 2012)
- Moffitt: “The cells we took from mice treated with PV-10 were indeed activated against B16 melanoma tumors. We demonstrated that by showing that they could be transferred to untreated mice with the same tumor and produce an antitumor response. This is the definitive way to test for a tumor-specific T-cell response.” Against MC-38 adenocarcinoma tumors, the T-cells from treated B16 mice had no significant effect. “This is a very specific response to the B16 tumor,” Dr. Pilon-Thomas said. (AACR 2013)
- Provectus: PV-10's immuno-ablative response is tantamount to "in situ vaccination" (SITC 2012). After all, isn't that what leads to systemic anti-tumor immunity?
- A 5 mL single-use vial costs tens of dollars to manufacture
- A melanoma patient may average 6 vials
- Early-stage liver trial patients thus far may have averaged 5-10 mL (receiving single injections of drug product)
- 1923: "The patient, a Chinaman with a carcinoma of the pancreas with complete biliary obstruction, showed no toxic effects after the intravenous injection of 100 mg. of the dye. In fact, while observing interest the injection of this beautifully colored “medicine” he stated that he felt much better and wanted more. Frequent injections on this patient gave no toxic effects and led to the subsequent injection of some two to three hundred others."
- Provectus: PV-10 is not metabolized in the body and has a 30-minute half-life once in the bloodstream.
- Melanoma/Provectus: Mild to moderate adverse events, mostly at the injection site (Phase 2)
- Liver/Provectus: Transient elevation of transaminases (Phase 1)
- No off-tumor cell killing, no tumor lysis syndrome
- Melanoma & Breast Cancer/Moffitt: "These studies have demonstrated that intralesional PV-10, in addition to reducing the growth of a directly injected tumor, leads to the induction of a robust anti-tumor T cell response and supports the use of PV-10 to induce systemic anti-tumor immunity for the treatment of metastatic melanoma and breast cancer." (AACR 2013)
- Colorectal/University of Illinois at Chicago: "Rose Bengal induced potent cell death in human and murine colon cancer cells in vitro. Intralesional injection in established tumors induced an anti-tumor immune response and significant tumor regressions in vivo. These studies establish that intralesional PV-10 therapy warrants further study as a potential immunotherapeutic agent in colorectal cancer and metastases." (SSO 2015)
I have not included the initial Phase 1 liver data because it only addresses PV-10's tumor ablation, and not yet on the drug's systemic effect.
F. No specific target, receptor or pathway
This item cannot be properly discussed at the current time because knowledge and discussion relies on the presentation/publications of the results of Moffitt Cancer Center's mechanism(s) of action study due later this year.
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