Immunotherapy includes a number of strategies that harness the immune system to help treat disease. Immunotherapy for cancer, as we know it, now relies on the activation of specific immune system cells known as T cells. Cancer drugs called immune checkpoint inhibitors act by removing the brakes imposed on T cells by tumors or by the body’s natural mechanisms for limiting their activation to prevent autoimmune disease.

In recent years, the U.S. Food and Drug Administration (FDA) has approved several immune checkpoint drugs for the treatment of various cancers. These drugs target proteins involved in activating the T cell response: PD-1, PD-L1, and CTLA4. Many clinical trials are testing drugs that target other immune checkpoint proteins (OX40, B7-H3, and LAG3, to name just a few), but no notable successes have been reported so far.

Now, some clinical investigators have turned their attention to a different arm of the immune system that could help treat cancer.

Harnessing an Ancient Immune Response

T cells are major players in the adaptive immune system—an arm of the immune system that “adapts” or educates itself to recognize highly specific targets (like mutant proteins in cancer cells or specific molecules found on viruses or other pathogens). This adaptive response takes a while to mount. Meanwhile, a more ancient arm of the immune system, the innate immune response, is not very specific, but provides very fast recognition of many kinds of pathogens, including viruses, bacteria, and parasites.

What has become clear is that the innate response also plays an integral role in the development of the adaptive response. The innate response involves cells (macrophages and dendritic cells) that may eventually present specific “foreign” molecules to T cells and initiate a specific, adaptive, response. When it comes to cancer, the problem is that the adaptive immune response is just not activated in in many patients. The reasons for this may be diverse, but in general, tumors that manage to dispel the adaptive immune response are known as immunologically “cold.”

In a new approach to cancer, scientists have hypothesized that a treatment strategy that activates the innate response could turn at least some immunologically “cold” tumors into “hot” ones. The innate immune response could be induced by mimicking an infection with foreign pathogens without actually introducing an infection.

Taking a “Toll” on Cancer

The key to this new treatment approach may be proteins known as toll-like receptors (TLRs), of which there are 10 different types. TLRs are found on the surface of macrophages—immune system cells that not only destroy incoming pathogens, but also may alert the adaptive immune system to an infection. Activation of TLRs occurs in response to sub-components of various invaders, but these components are often of a rather generic nature; they typically include certain types of bacterial or viral proteins, or simply nucleic acids (such as DNA or RNA). For example, a TLR known as TLR9 recognizes a motif in DNA sequences known as CpG, which is found far more frequently in bacterial than in our own DNA. In a healthy cell, DNA is found in in the nucleus and mitochondria, but a cell infected by a virus or intracellular bacteria will have the pathogen’s DNA in its cytosol (the liquid in a cell), inducing an innate immune response.

When a TLR9 “agonist,” such as a DNA molecule enriched in CpG , is injected into a tumor, this may trigger rapid activation of macrophages and dendritic cells (DCs) that express TLR9. The macrophages may directly destroy the infected cells, but, together with DCs, they may be able to alert T cells residing in the tumor or draining lymph nodes, and thus promote an adaptive immune response.

Indeed, earlier this year, a publication from Stanford scientist Ronald Levy, MD, showed stunning activity of CpG when combined with an anti-OX40 immune checkpoint drug in mice representing various human cancers. This work created a lot of excitement.

Even before that publication, TLR9 agonists very similar to CpG were in clinical trials. Excellent results have been reported for a CpG-type molecule known as SD-101 in slow-growing (indolent) lymphomas. In a clinical trial, 29 patients received low-dose irradiation and injections of SD-101 directly into their tumors (intratumoral injections). All patients experienced reduction in the size of the injected tumor, and most (24 patients) also experienced shrinking of other un-injected tumors.

A small trial showed really good results for patients with metastatic melanoma. Out of nine patients, eight (78%) had a durable response to SD-101 combined with intravenous delivery of the anti-PD-1 immune checkpoint drug pembrolizumab (Keytruda). Unfortunately, of 13 additional patients who had already been treated with anti-PD-1 drugs, only two have responded to the combination of SD-101 and pembrolizumab.

Another TLR9 agonist, IMO-2125, was also tested in metastatic melanoma, with the addition of intravenous ipilimumab (Yervoy), an anti-CTLA4 immune checkpoint drug. In this trial, 15 patients received intratumoral injections of IMO-2125 and ipilimumab. The researchers reported last June that 47% of the patients had significant reduction of tumor burden, and the overall disease control rate was 67%. Two patients had a complete response. Some of the patients had been treated with anti-PD-1 drugs prior to entry in this trial.

The following TLR9 agonists are in trials, mostly in combination with immune checkpoint drugs: SD-101, IMO-2125, MGN1703 (Lefitolimod), and DV281. Other TLR agonists are also in trials, particularly activators of TLR7/8, including NKTR-262 and MEDI9197.

The Potential of STING Agonists

The other key player in the body’s innate immune response is known as the stimulator of interferon genes (STING) pathway. The STING pathway was first discovered as a response to viral infections; it senses viral DNA in the cytosol of infected cells. As the name reflects, activation of the protein interferon, a very potent immune system stimulator, is a hallmark of this pathway, which could also play a role in cancer treatment.

In the STING pathway, a specific protein called cGAS recognizes DNA in the cytosol of an infected cell. cGAS produces a molecule called cGAMP, which activates the protein STING, for which the entire pathway is named. STING activates dendritic cells, which in turn may lead to the activation of the adaptive immune response involving T cells. There is evidence that the STING pathway may be involved in the efficacy of radiation as cancer treatment; the nuclei of cancer cells may break down during radiation, releasing DNA and activating the STING pathway.

Drugs that activate STING, or STING “agonists,” are now in clinical trials. These are either in a ring-shaped molecular structure known as a cyclic dinucleotide (like cGAMP) or some engineered agonist molecules that have been shown to activate production of interferon.

One has to be careful with these new drugs because systemic activation of interferon may cause strong inflammatory and autoimmune responses. Stimulation of STING should be transient, not chronic, and use of STING agonists is limited to intratumoral injections, similar to TLR9, in order to avoid potentially severe systemic effects. The STING agonists currently being tested in trials are ADU-S100/MIW815 and MK-1454, but additional molecules are advancing toward clinical development.