Warming “Cold” Melanoma with TLR9 Agonists

For patients with metastatic melanoma whose disease is refractory to PD-1 blockade, the addition of CMP-001 (Checkmate Pharmaceuticals), an investigational TLR9 agonist, could potentially mitigate this resistance. Data from an ongoing phase I study evaluating CMP-001 alongside pembrolizumab (Keytruda; Merck) were presented on April 17 by Mohammed Milhem, MBBS, of Holden Comprehensive Cancer Center in Iowa City, IA, during the American Association for Cancer Research (AACR) Annual Meeting 2018 in Chicago, IL.

CMP-001, a CpG-A oligodeoxynucleotide (ODN), is a synthetic ligand for TLR9, stimulating the latter's activity in immature plasmacytoid dendritic cells (pDC), which tumors recruit to help maintain an immunosuppressive microenvironment. TLR9 signaling induces these pDCs to secrete type I interferons and inflammatory chemokines, facilitating the infiltration of cytotoxic T cells and other immune cells that turn an immunologically “cold” tumor “hot,” making it more receptive to therapy.

There are three major CpG classes of ODNs, but only Class A “spontaneously forms a nanoparticle and activates TLR9 as a multimeric structure,” explained Arthur Krieg, MD, Checkmate's chief executive officer. “Consequently, this class induces very high levels of IFNα, which is associated with the transcriptional signature in tumors that are responsive to checkpoint blockade.” For enhanced efficacy, CMP-001 is encapsulated in a viruslike particle, he added, “to better trick the immune system into attacking tumors the same way it would viruses.”

The study enrolled 69 patients whose disease had progressed on, or never responded to, pembrolizumab monotherapy. Each received CMP-001 injected directly into accessible lesions, in combination with pembrolizumab. Milhem reported that 15 patients responded—two completely—to treatment, according to RECIST criteria. Another three patients who remained on therapy despite initial disease progression achieved iRECIST responses. The median duration of response has not been reached.

Importantly, Milhem noted, treatment with CMP-001 produced both local and systemic effects, with the investigators observing shrinkage of even noninjected cutaneous, nodal, hepatic, and splenic metastases. The latter occurrence is “a hallmark of successful intratumoral immunotherapy,” he said. “In fact, the regression of injected versus noninjected lesions that we saw was pretty similar.”

To study investigator Antoni Ribas, MD, PhD, of the University of California, Los Angeles, “it's impressive that we were able to maintain PD-1 blockade for patients with disease progression, inject some peripheral lesions with CMP-001, and see responses.”

Another investigational TLR9 agonist highlighted at the AACR meeting was SD-101 (Dynavax), a CpG-C ODN. This class “is also effective at inducing IFNα, and helps with pDC maturation,” said Robert Janssen, MD, Dynavax's chief medical officer. In an ongoing phase I trial, among 13 patients with metastatic melanoma that progressed on prior PD-1 blockade, two achieved partial responses to intratumorally injected SD-101 plus pembrolizumab; five more had stable disease. In another cohort of nine patients who had not previously received PD-1 blockade, the estimated 12-month progression-free survival (PFS) with this combination was 88%.

“The historical comparison here is [PFS of] 44% at 6 monthson pembrolizumab monotherapy,” Janssen said, “so webelieve we're seeing some durable responses in this population. Starting with combination therapy up-front makes a lot of sense, we think.”

Both CMP-001 and SD-101 were well tolerated, with patients mainly experiencing flulike symptoms and hypotension, which were transient and readily managed. In addition, despite concerns about TLR9 signaling potentially increasing the frequency and severity of autoimmune disorders, “so far, we're not seeing that this is the case, at least in our study,” Janssen said.

TLR9 agonists have come a long way since 2007, Krieg observed, when PF-3512676, which he developed at Coley Pharmaceuticals and licensed to Pfizer, failed in phase III trials in advanced non–small cell lung cancer. “We learned, subsequently, that the T cells induced with our therapy had PD-1 on their surface, but there were no anti–PD-1 agents in development then,” he said. As well, PF-3512676 was delivered subcutaneously, and “we now know that the intratumoral route is the most direct way to get a focused immune response.”

Ribas agreed, observing that until recently, “the general opinion has been that systemic therapy is necessary if it's going to work, especially in the metastatic setting; there's no role for locally administered agents.”

“I still hear many people saying that intratumoral therapies only have intratumoral effects,” Krieg remarked. “That's been the story, but I do think people will be convinced by our data showing you can in fact get systemic responses too.” –Alissa Poh

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