February 21, 2014

It's all about the T-cells

I'm looking forward to reading Moffitt Cancer Center's American Association for Cancer Research ("AACR") annual meeting abstract next month, viewing the associated poster in April, and learning about what if anything they present at the American Society of Clinical Oncology ("ASCO") annual meeting in May/June. I presume they'll present something at ASCO because of Sondak's already scheduled PV-10 presentation at the 4th European Post-Chicago Melanoma/Skin Cancer Meeting. See Moffitt @ ASCO 2014? (February 10, 2014) under the blog's News tab.

There are three topics of their possible work I hope their poster presentation at AACR and any potential presentation(s) at ASCO would elucidate:
  1. PV-10's "mechanism of immune response," or the mechanism by which the drug induces systemic immunity (I think PV-10's primary mechanism of action, rapid tumor ablation following injection, is understood),
  2. Improved responses (i.e., tumor destruction and/or shrinkage) from combining PV-10 and other immunotherapies,
  3. PV-10's role and responsibility with respect to adoptive cell therapy ("ACT").
Let's re-visit the Discussion section of Moffitt's July 2013 PLoS paper Intralesional Injection of Rose Bengal Induces a Systemic Tumor-Specific Immune Response in Murine Models of Melanoma and Breast Cancer.
Click on the figure to enlarge it: Discussion, portion 1
Click on the figure to enlarge it: Discussion, portion 2
While Provectus pursues the initial local path to approval for PV-10 of locally advanced cutaneous melanoma, Moffitt is more interested in PV-10's systemic properties and benefit, and more than likely its application to patients with metastatic melanoma and other late-stage solid tumor cancer indications. Some observations of the above, which was first presented at AACR 2013 and discussed more in the paper:

- First, in murine model work, Moffitt confirmed PV-10 generated an anti-tumor immune response that shrunk or destroyed untreated tumors (red underlined portions 1, 2 and 3 in paragraphs 1 and 2). They observed the systemic potential of PV-10 for both breast cancer and melanoma.

- Second, they hypothesized that large amounts of tumor debris created by the rapid ablation that followed PV-10's injection into tumors, debris containing antigens (thus, large amounts of debris should mean large numbers of antigens), are taken up by dendritic cells ("DCs") (red underlined portion 4 in paragraph 3). DCs, antigen-presenting cells, present (display) antigens they've taken up to the body's immune system's T-cells.

- Third, Moffitt suggested combining PV-10 with other immunotherapies may lead to better results in patients with metastatic melanoma (red underlined portion 5 in paragraph 4).

- Finally, fourth, they demonstrated immunity could be transferred from mice with PV-10 treated tumors to mice with untreated tumors, hypothesizing (I think) that more and better T-cells could be created using PV-10 (better ones) together with ACT (more of these better ones) to then use on more than one patient (red underlined portions 5 and 6 in paragraph 4).

There are T-cells, and then there are T-cells. There are different types of T-cells, each with a distinct function: helper, cytotoxic, memory, regulatory, natural killer, and mucosal associated invariant. "Cytotoxic T cells ("CTLs") destroy virally infected cells and tumor cells." "Regulatory T cells, formerly known as suppressor T cells, are crucial for the maintenance of immunological tolerance." "Natural killer T cells ("NKT cells")...are also able to recognize and eliminate some tumor cells and cells infected with herpes viruses."

CTLA-4 and PD-1 cell receptors are the so-called brakes of the immune system, limiting its response. Taking the brakes off by inhibiting these blockade receptors (with anti-CTLA-4/PD-1 agents) allows for a more active and vigilant immune system. CTLA-4 and PD-1 agents, I think, help out with or activate these regulatory T-cells.

PV-10, on the other hand, I think, helps out with or activates CTLs, by virtue of the drug's rapid ablation causing tumor debris containing antigens to be taken up by DCs that then display them to this type of T-cell. "For long it has been discussed whether ablated tumor debris is able to induce a systemic immune response."

So, while activating regulatory T-cells and CTLs (cytotoxic T-cells) both may result in tumor destruction and shrinkage, regulatory T-cell activation by checkpoint inhibitors is not permanent and eventually resisted or overcome, whereas CTL activation by PV-10 may result in [permanent?] immunity.

"CTLs specific for tumor antigens play a major role in the immunity against cancer." Will Moffitt show PV-10 specifically activates these CTLs?

If the checkpoint inhibitors remove the brakes of the immune system, allowing it to shrink tumors but not activate the specific T-cells responsible for destroying tumor cells, the utility of combining them with PV-10 would be to have these inhibitors reduce tumor burden and thus the "weight" on the immune system, thereby allowing it to be better stimulated by PV-10. Such combination use would be very helpful for late stage metastatic melanoma patients where tumor burden is high.

Moffitt has conducted trial work on both MK-3475 (Merck) and nivolumab (Bristol-Myers) PD-1 agents. Will Moffitt present combination work with PV-10 involving one of these agents?

"Adoptive T cell therapy involves the isolation and ex vivo expansion of tumor specific T cells to achieve greater number of T cells than what could be obtained by vaccination alone.  The tumor specific T cells are then infused into patients with cancer in an attempt to give their immune system the ability to overwhelm remaining tumor via T cells which can attack and kill cancer.  There are many forms of adoptive T cell therapy being used for cancer treatment; culturing tumor infiltrating lymphocytes or TIL, isolating and expanding one particular T cell or clone, and even using T cells that have been engineered to potently recognize and attack tumors" (Source: Tumor Vaccine Group, UW Medicine). The current approaches for ACT seem to focus on ex vivo (out of the tumor/body) improvements to T-cells; that is, endeavoring to make more of them better external to the patient.

But, as Moffitt first introduced in the February Cancer Watch article, per Dr. Sarnaik, PV-10 appears to improve the quality of T lymphocytes (cytotoxic?). It does this in vivo (in the tumor/body), of course. Perhaps Moffitt's novel approach is to utilize T-cells taken directly from the patient’s blood after they have received a PV-10 injection, which primes the tumor antigen specific T-cells first. Then, with active immunization already established by PV-10, they expand the number of those T-cells in the lab to greater numbers for therapeutic infusion, and thus even greater response success.

March (abstract), April (presentation), May (abstract(s)?), June (presentation(s)?)...

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