March 9, 2014

"...a significant increase in the number of DCs infiltrating the tumor-draining lymph nodes after IL injection of PV-10."

Further (repeated) reading of Moffitt's AACR 2014 abstract drew me to: "...Further preclinical translational testing has shown that treatment of murine B16 cells with PV-10 leads to release of HMGB1, a soluble Damage Associated Molecule Pattern (DAMP) that is important for activation of dendritic cells (DCs). In the murine B16 melanoma model, there is a significant increase in the number of DCs infiltrating the tumor-draining lymph nodes after IL injection of PV-10. These findings suggest that PV-10 treatment leads to the release of DC activating factors and DC recruitment. Further studies to determine the role of PV-10 on T cell activation are ongoing..." {bolded underlined emphasis is mine}

I'm particularly interested in this, "[i]n the murine B16 melanoma model, there is a significant increase in the number of DCs infiltrating the tumor-draining lymph nodes after IL injection of PV-10," as it relates to:
  1. Overcoming resistance to cancer treatments, and
  2. Breast cancer.
Tumor-draining lymph nodes, or "TDLNs," are "[l]ymph nodes that lie immediately downstream of tumors." Lymph nodes act as filters for the body’s lymphatic drainage system, catching cancer cells in the fluid draining away from a tumor. It's easy to understand the importance of the lymph nodes to metastatic disease, and thus the relationship the TDLNs (lymph nodes where cancer cells themselves have infiltrated, grow in number, and journey to near and distant parts of the body) have with cancer. Lymph nodes are an immune system organ. What organs make up the immune system? Bone marrow, thymus, spleen and lymph nodes. "Lymph nodes are a bit like the spleen, but instead of filtering blood, they filter lymph. Lymph is composed of fluids which drain from tissues. It is collected at various locations throughout the body and circulates through a series of lymph nodes, eventually returning to the blood for circulation" (previously linked source).

But, the TDLNs are immune-privileged sites. "Immune responses and associated inflammation in certain parts of the body, including brain, eye, testes, placenta, and fetus, carry a high risk of lethal organ dysfunction or reproductive failure. These tissues, which have evolved to be protected, to a variable degree, from immune responses, are called immune privileged sites."

Once cancer cells from upstream tumors enter downstream lymph nodes (i.e., enter the TDLNs), the disease becomes ever so more dangerous. This infiltration of the TDLNs by diseased cells, and thus into an immune-privileged area where a protective immune response to the invaders is not sufficiently or strongly initiated, allows the cancer cells (I think) to grow much more unfettered and un-fought by the body's immune system than they potentially would elsewhere in the body. "Lymph nodes that lie immediately downstream of tumors [tumor-draining lymph nodes (TDLNs)] undergo profound alterations due to the presence of the upstream tumor. The antigen-presenting cell population in TDLNs becomes modified such that tumor-derived antigens are cross-presented by host cells in a tolerizing fashion. In addition, the number and suppressor activity of regulatory T cells (Tregs) are increased in the TDLN. Emerging evidence suggests that some of these Tregs may be generated de novo against specific tumor-derived antigens, and thus they arise as a direct consequence of antigen presentation in the TDLN. Others may represent Tregs against self-antigens, which undergo preferential activation in the tolerogenic milieu of the TDLN. The TDLN thus becomes an anatomic context in which presentation of new antigens not only fails to elicit a protective immune response but also actively creates systemic tolerance. In this regard, the TDLN displays features analogous to classical immune privilege. Accumulating evidence thus suggests that the TDLNs, although small in size, may exert a profound tolerizing influence on the rest of the immune system. These mechanisms will need to be interrupted in order for clinical anti-tumor immunotherapy to be successful." {bolded emphasis is mine}

Thus, preventing the TDLNs from naturally suppressing what otherwise would be a normal immune response to tumor fluid or fragments or discharge emanating from an upstream tumor would be key, as noted above, to more successful anti-tumor immunotherapy: "Regional lymph nodes are the first site for melanoma metastases. The sentinel node (SN), on the direct lymphatic drainage pathway, which usually harbors first metastases, demonstrates significant suppression in its ability to respond to antigenic stimulation...Antigen presentation by dendritic cells (DCs) is the most potent means to initiate a T cell immunity."  So, if an otherwise immune-privileged site like the TDLNs are unable to mount an immune fight or response, success likely would be achieved by encouraging the infiltration of DCs into these lymphoid organs (i.e., the TDLNs) to start and continue the fight.

Moffitt's AACR 2014 abstract: "In the murine B16 melanoma model, there is a significant increase in the number of DCs infiltrating the tumor-draining lymph nodes after IL injection of PV-10."

But, is a systemic immunotherapy able to achieve the recruitment of DCs to the TDLNs, or is a local therapy better suited? "In recent years, it has become apparent that immunoregulatory processes influence cancer development. The key players in tumor progression are mainly present in the microenvironment of the tumor and the draining lymph nodes. Interventions aimed at shifting tumor-promoting actions toward effective tumor-eradicating immunity are thus foremost required locally. As immune-modulating therapy has been shown to cause many adverse side effects when administered systemically, we strongly advocate the further development of local treatment for cancer immunotherapy" {Bolded emphasis is mine}

As Craig has said for a while the path to defeating cancer, a systemic disease, is through local therapy that has systemic properties. Rapid ablation of injected tumors upstream from the TDLNs creates tumor fragments (antigens) that are taken up from antigen presenting DCs that infiltrate the TDLNs to create an immune response in an area that desperately needs one.

PV-10's rapid ablations fights cancer's foot soldiers on the front lines (i.e., the injected tumors). By getting the body to send its own solders into the TDLNs to fight cancer cells there, metastatic disease around the body has its supply lines cut. PV-10 breaks tolerance. Is Moffitt showing antigen presenting DCs migrating (infiltrating) into the "tolerizing" environment of a TDLN and overcoming tolerance (resistance)? Have they figured the mechanism to overcoming tolerance (resistance); that the migration of antigen presenting DCs is what breaks tolerance? Of course, the sentence in the Moffitt 2014 abstract is based on their murine model (pre-clinical work).

Now, for breast cancer. Stanford's Dr. Peter Lee, M.D. notes that: "Whether TDLNs are invaded by cancer cells is a key prognostic indicator for patients with breast and other cancers. Lymph nodes are immune organs and TDLNs are key sites of tumor-immune interactions...TDLNs may be immunologically altered and demonstrated the clinical significance of T cell and dendritic cell (DC) decreases in predicting relapse in breast cancer." Or, here too.

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: "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." {Bolded emphasis is mine}

It's interesting to note Moffitt's abstract (i.e., TDLNs) in the context of the breast cancer update in Provectus' corporate website presentation. See the blog's News tab: Phase 2 Recurrent Breast Cancer Trial Prep Underway? (March 6, 2014).

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