On A Tumor’s Turf

In Biologics, Cancer, Clinical Trials, Drug Development, Drug Targets, Mechanism of Action, Small Molecule Drugs, The WEEKLY by Emily Burke

TACKLING THE SPACE AROUND SOLID TUMORS

Covering the science behind T-cell-based immunotherapies has been the name of the game for our past couple of issues. CAR-T and TCR therapies show significant promise in early phase blood cancer clinical trials, but what about solid tumors?

Previously mentioned Juno Therapeutics’ (Seattle, WA) Armored CAR technology has declared war on tumors, and as you will read below, there are plenty of interesting battle grounds to choose from. Let’s find out why solid tumors are more difficult to treat than leukemia, lymphoma, and myeloma and where the biopharma industry is staging its fight.

SOLID TUMORS DEFINED

A solid tumor is defined as an abnormal mass of tissue that usually does not contain cysts or liquid areas according to the National Cancer Institute.

Solid tumors may be classified as:

  • Benign (noncancerous) if they do not invade nearby tissue or spread to other parts of the body.
  • Malignant (cancerous) if they invade and destroy nearby tissue and spread to other parts of the body.
THE TUMOR MICROENVIRONMENT

The tumor microenvironment (TME) describes the cellular environment in which the tumor exists. Different than healthy tissue, the TME may contribute to tumor growth and complicate treatment strategies.

The TME is typically immunosuppressive—that is, it actively attempts to prevent the immune system from recognizing a tumor as harmful. One of the factors contributing to immunosuppression is the presence of “suppressor cells”— white blood cells that subdue rather than activate the immune system. These include tongue-twister names such as myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T-cells.

Suppressor cells release signaling molecules that “turn down” activated immune cells within the immediate area. They also release growth factors that increase blood vessel growth into the tumor, which helps the tumor to survive. The TME also inhibits the display of antigens (tumor-specific proteins) on the tumor surface, which are necessary to activate killer T-cells against cancer.

Harnessing the space around the tumor might herald some fighters in the field. Surface Oncology (Cambridge, MA) is using a combination of proprietary technologies to modify the TME. These modifications include blocking suppressor cells, stopping immunosuppressive signaling molecules, and improving the presentation of antigens on tumor cell surfaces. Currently in the preclinical stage, Surface recently partnered with Novartis (Basel, Switzerland) to further develop their platforms. Clinical development candidates are expected to be released in the near future.

BACTERIA TO THE RESCUE?

In the context of immunotherapies, most people use the term “cell therapy” to refer to the activation or engineering of  T-cells to attack cancer. Aduro Biotech (Berkeley, CA) puts a new spin on the concept by using engineered bacteria cells to induce a cancer-specific immune response—the technology aims to get around the problem of poor antigen presentation. The concept: to uncloak tumor cells so they are more easily identifiable by the immune system.

Scientists at Aduro have taken the pathogenic bacterium Listeria monocytogenes and modified it in two ways:

  • Safety modification: Two genes that are critical to its ability to infect liver cells were deleted.
  • Efficacy modification: Two genes that code for tumor-specific antigens were added.

When delivered to a patient, these cells should activate tumor-specific T-cells to attack. Aduro is currently conducting early stage clinical trials using engineered Listeria monocytogenes against pancreatic cancer, non-small cell lung cancer, ovarian cancer, and mesothelioma.

THE STING PATHWAY

Aduro Biotech is also working on a small molecule immune system activator to help overcome the immunosuppressive TME. These small molecules are modified versions of naturally occurring molecules that activate a pathway known as STING: Stimulator of INterferon Gene.

Activation of the STING pathway results in the production of immune-activating signaling molecules. Preclinical studies suggest that delivering the STING-activating molecules near tumor sites invokes the immune system to recognize and respond to cancer cells.

If these possibilities become a reality, the battleground around a solid tumor may be taken by the world of drug discovery, adding to the arsenal of immunotherapies in our fight against cancer.