The stunning comeback of TLR-9

Given the release of encouraging data by Idera Pharma’s TLR-9 program IMO-2125 at this year’s ESMO, it is time to review this once again promising cancer target. TLR-9 belongs to the class of so called Toll-like receptors or TLR. TLRs are pattern-recognition receptors that react to distinct molecular patterns of various pathogens in order to activate the immune response. TLR-9 in particular is expressed on endosome membranes of B-cells and plasmacytoid dendritic cells and stimulates specific immune reactions through the activation of inflammation-like innate responses. It binds to unmethylated CpG dinucleotides, a common structure found in microbial DNA. The general idea in cancer therapy is to use synthetic oligonucleotides containing CpG motifs in order to trigger the receptor and activate macrophages, dendritic cells (DC) and B cells, as well as the production of cytokines, chemokines, and immunoglobulins. The idea is to turn “cold” tumors into “hot” tumors. TLR-9 agonists are administered locally into the tumor environment where they kick the immune system into high gear. Once the immune system learns to react to local cancer antigens, the effect should also spread to the more distant metastases in the body.

Early approaches fail

Clinical studies involving TLR-9 agonists in monotherapy settings as well as in combination with chemotherapy have been pursued for over a decade. Unfortunately, early results were mixed at best. As seen with many approaches, the immunosuppressive environment of the tumor turned out to be a major obstacle for the therapy to be effective. IMO-2055 for example had been tested as a monotherapy and in combination various chemotherapies but with limited success. The same applies to SD101, a TLR-9 agonist developed by Dynavax, which too entered the clinic a decade ago. Germany based Mologen, which currently runs a large phase III study with its TLR-9 agonist lefitolimod in metastatic colorectal cancer also had to report a failed monotherapy trial in small cell lung cancer.

The tide turns

With the arrival of PD1 and CTLA-4, the tide started to turn for TLR-9. It turned out that pushing the immune system’s gas pedal without first releasing the brakes was rather futile. But now that clinicians have the tools available to release the breaks, pushing the gas pedal seems to become a winning strategy. Indeed, 2017 so far is the year of TLR-9 success stories:

Earlier in 2017, Dynavax reported encouraging clinical data from SD-101 at the International Congress on Targeted Anticancer Therapies. In a Phase 1b/2 study of SD-1001 in combination with pembrolizumab in PD-1 naïve patients with metastatic melanoma, the company reported an Overall Response Rate (ORR) of 86%, including a 29% complete response rate and a 57% partial response rate. In 10 patients with progressive disease who initiated KEYTRUDA anti-PD-1 monotherapy prior to enrollment, one PR was observed and five patients had stable disease (SD) while receiving KEYTRUDA and SD-101, with four of the 10 patients experiencing target tumor shrinkage.

Idera Pharma follows up with more positive data

And now at ESMO, Idera Pharma followed up with more data on its phase I study of IMO-2125 in combination with Ipilimumab. The combination achieved an Overall Response Rate of 44% in melanoma patients which were refractory to anti-PD1 therapy. From the press release:

  • Nine patients were treated at the Recommended Phase 2 Dose (RP2D) of 8 mg IMO-2125 (in combination with ipilimumab)
  • Confirmed RECIST v1.1 responses (including 1 Complete Response (CR) ≥ 1 year) were observed in 4 of these 9 subjects (44%);
  • Overall 6 patients out of 9 treated at the RP2D (67%) experienced disease control (CR, PR, or durable SD);
  • A RECIST v1.1 PR of > 1 year duration is ongoing in a patient treated with IMO-2125 4 mg (in combination with ipilimumab);
  • IMO-2125 in combination with ipilimumab is tolerable at all dose levels studied
  • IMO-2125 was safely administered via deep injection (using interventional radiology guidance) in patients lacking superficially accessible disease for injection
  • Dose escalation with IMO-2125 and pembrolizumab is ongoing; one patient has an ongoing PR by RECIST (v1.1), and;
  • An abstract highlighting translational findings from the trial has been accepted as an oral presentation for the upcoming Society for Immunotherapy of Cancer (SITC) meeting in November.

“The majority of patients with solid tumors do not respond to anti-PD-1 therapy and the published response rate to ipilimumab alone in anti-PD-1 refractory melanoma is only 10-13%; to be seeing 6 out of 9 patients experiencing clear disease control is extremely exciting,” stated Adi Diab, M.D., Lead Trial Investigator, Assistant Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine, University of Texas, MD Anderson Cancer Center.

Although the study samples are still small, these datapoints are promising and suggest that TLR-9/PD-1/CTLA-4 combos could generate more positive headlines going forward.

Another indication of the potential of this approach is the fact that Arthur Krieg has re-entered the field with a startup called Checkmate Pharmaceuticals where he develops a TLR9 agonist in-licensed from Kuros (formerly Cytos) in combination with pembrolizumab. Krieg, a veteran in the TLR-9 field, had co-founded Coley Pharma which had pioneered the TLR-9 approach in cancer therapy. The company was sold to Pfizer in 2007 but the TLR-9 program was stopped after it too failed in the clinic. It seems that Krieg also understands that with the arrival of checkpoint inhibitors, the tide is turning for TLR-9.