The Tumor Micro Environment is Under a lot of Pressure

 

 

 

The tumor micro-environment is a hot topic these days. I suspect it has a lot to do with the rise of immunotherapy and the delta in performance of CAR-T therapies between hematological cancers versus solid tumors, which represent the majority of cancers. This year’s AACR meeting is producing more than a few informative “tumor microenvironment 101” posters, which describe the myriad of hurdles that a tumor places between a cancer therapy and the cancer cells the therapy is meant to kill. While the impact of the tumor micro-environment on cancer therapy success might be news for many in the cancer community, at CytImmune, we’ve been working on the best way to break through the tumor micro-environment for more than a decade. And we’ve had great success.

Here’s what we know, and what others still seem to be missing. Before we can fully overcome dis-regulation of T-cells, dendridic cells, and fibroblasts; before we can completely break down extracellular matrix challenges, including excess hyaluron, collagen, and fibroblasts; before we can get molecularly targeted therapies to reach their maximum effectiveness; we must address the high interstitial fluid pressure (IFP) inside the tumor caused by the leaky blood vessels present in all solid tumors.

That all solid tumors have leaky blood vessels, unique in the body, is thirty-year-old news. This observation gave rise to idea of the EPR Effect (Enhanced Permeability and Retention), which in turn spawned a significant investment in efforts to use these leaky blood vessels to access the tumor’s interior. What was not, and is still not appreciated, is the degree to which these leaky blood vessels increase tumor IFP, and push cancer therapies away. Over a time period in which numerous therapies designed to take advantage of the EPR effect have failed, oncologists have moved on to newer and exciting therapies including immunotherapy and molecularly targeted personalized medicine. While many in the research community moved on, the challenge of high internal tumor pressure remains. [click here for more information on high IFP and the EPR effect].

While we recognize and applaud the progress of others in understanding the tumor micro-environment, and the development of tools to attack it, we strongly urge our colleagues to remember and consider the role that the leaky tumor vasculature plays in shaping the tumor micro-environment and in limiting the effectiveness of cancer therapies.

At CytImmune, across multiple solid tumor animal models, we have been able to destroy the tumor vasculature, induce increased vascular leakiness at the sites of primary and secondary tumors, and eliminate high IFP. In doing so, we have documented a dramatic increase in the concentration of follow-on anti-cancer therapy inside the tumor after destruction of the tumor vasculature and the elimination of high tumor pressure.

We believe this achievement will strongly complement other therapeutic efforts. If we can break down the extracellular matrix, how much better will cancer therapies be if we also eliminate high IFP? If we can deliver therapies to activate immune cells inside the tumor, how much better would those therapies be if we were able to get four, five or six times their concentration deep into the heart of the tumor?  To defeat the tumor micro-environment, and unleash the full potential of old and new cancer therapies, we need to destroy the tumor vasculature and eliminated high tumor IFP.

MORE ABOUT CTYIMMUNE’s WORK

The Challenge

Agents that alter or destroy blood vessels do not discriminate between healthy and tumor blood vessels. The potentially life-threatening side effects of such systemically administered vascular disruption agents (VDAs) have thus far prevented their systemic use. However, in patients with in-transit tumors on their limbs, surgical oncologists in Europe are routinely isolating that limb, hooking its major blood supply to a heart-lung machine, and infusing an otherwise toxic dose of the cytokine, tumor necrosis factor alpha (TNF) followed by chemotherapy [1]. In a variety of tumor indications, one treatment has been shown to result in dramatic local tumor shrinkage in approximately 85% of cancer patients [1]. This dramatic success has been attributed to the biologic action of TNF, which causes apoptosis of vascular endothelial cells, resulting in a significant drop in tumor IFP, allowing more follow-on chemotherapy to sequester in the tumor, which in turn results in better tumor regression [1]. The challenge has been to deliver TNF systemically at a therapeutic dose, approximately 1 mg that avoids its life-threatening side effects.

Numerous clinical trials conducted with human recombinant TNF have shown that the maximum tolerated dose of systemically administered TNF is approximately 0.4 mg per dose [2]. With higher doses, patients experience vascular leak that requires medical treatment, with some patients experiencing the constellation of clinical symptoms consistent with septic shock.

Our Solution

We have designed a nanomedicine platform whose core is a 27 nm particle of gold that is decorated with TNF and a linear form of polyethylene glycol (PEG) with a distal thiol group (PEG-Thiol) [3]. Both molecules bind independently to the gold nanoparticles through available thiols forming a dative covalent bond. The resultant TNF-bound, PEGylated gold nanoparticle drug has been assigned the name, CYT-6091.

The gold-bound TNF serves two functions on CYT-6091. First, with the passive extravasation of CYT-6091 through the tumor neovasculature (the EPR effect), the gold-bound TNF binds to TNFR1 receptors found on the endothelial cells that comprise the tumor neovasculature. Once TNF binds to its receptor, TNF then exerts its biologic action; apoptosis of these endothelial cells, destroying these blood vessels. Thus, TNF on CYT-6091 serves as an active tumor targeting ligand and as a vascular disrupting agent (a VDA).

Our Findings

Most recently, we have studied CYT-6091 in using a murine tumor models and two genetically engineered mouse models (GEMMs) of pancreatic cancer, the MEN1 knockout (KO) for pancreatic neuroendocrine tumor (PNET) and Kras/p53 for pancreatic ductal adenocarcinoma (PDAC). Each murine model system provided specific data to support our hypothesized mechanism of action of CYT-6091 as a VDA.

For example, in the 4T1 murine mammary tumor model, a significant drop in tumor IFP was seen following CYT-6091 treatment [5], while in MC-38 murine colon carcinoma tumors, tumor specific vascular leak was observed [6]. However, we were concerned that the tumor vasculature supporting these implanted murine cancer cell tumors might not reflect the tumor vascular network found in naturally occurring tumors. We reasoned that GEMMs are the ideal models to evaluate the effect of CYT-6091 on the tumor vasculature.

Using GEMMs, we found a 6-fold increase in the tumor levels of the chemotherapy paclitaxel in PNET tumors after administration of CYT-6091 22 hr before pacliatxel compared with paclitaxel alone. Using dynamic contrast enhanced magnetic imaging resonance, CYT-6091 treatment caused significant vascular leak in PNET tumors, not seen in muscle or in PBS-treated control animals. [7] Based on these preclinical data, we are planning a phase II study in patients with pancreatic cancer, combining standard-of-care chemotherapy ± CYT-6091.

SOURCES

  1. Grünhagen, D.J. de Wilt, J.H.W., ten Hagen, T.L.M. Eggermont, A.M.M. Technology Insight: Utility of TNF-Alpha-Based Isolated Limb Perfusion to Avoid Amputation for Irresectable Extremity Tumors, Nat Clin Pract Oncol 3(2): 94-103 (2006).
  2. Roberts, N.J., Zhou, S., Diaz Jr., L.A., Holdhoff, M. Systemic use of tumor necrosis factor alpha as an anticancer agent. Oncotarget 2: 739-751 (2011).
  3. 7. Paciotti , G.F., Myer, L., Weinreich, D., Goia, D., Pavel, N., McLaughlin, R.E., Tamarkin, L. Colloidal Gold: A Novel Nanoparticle Vector for Tumor Directed Drug Delivery, Drug Delivery 11:169–183 (2004).
  4. 8. Libutti, S.K., Paciotti, G.F., Byrnes, A.A., Alexander, Jr., H.R., Gannon, W.E., Walker, M., Seidel, G.D., Yuldasheva, N., and Tamarkin, L. Phase I and pharmacokinetic studies of CYT-6091, a novel pegylated colloidal gold-rhTNF nanomedicine. Clin. Cancer Res., 16, 6139-6149 (2010).
  5. Koonce NA, Quick CM, Hardee ME et al. Combination of gold nanoparticle-conjugated tumor necrosis factor-alpha and radiation therapy results in a synergistic antitumor response in murine carcinoma models. Int. J. Radiat. Oncol. Biol. Phys., 93, 590-596 (2015).
  6. Farma, J.M., Puhlmann, M., Soriano, P.A., Cox, D., Paciotti, G.F., Tamarkin, L., Alexander, H.R. Direct evidence for rapid and selective induction of tumor neovascular permeability by tumor necrosis factor and a novel derivative, colloidal gold bound tumor necrosis factor. Int. J. Cancer 120: 2474-2480 (2007).
  7. Data to be published later in 2017
*For more information about CytImmune, CYT-6091, or other CytImmune products, please visit http://cytimmune.com
**The FDA has not approved CYT-6091 for use or sale outside a clinical trial.

 

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s