Developing a new approach for cancer immunotherapy

Learn More

About Checkmate

Checkmate Pharma is developing a new approach for cancer immunotherapy, by specifically activating the immune system to recognize and kill tumor cells throughout the body, without harming normal tissues.

Learn How Checkmate Is Heating Up Cancer Immunotherapy


Checkmate’s drug is a CpG-A that converts immunologically “cold” tumors to “hot”


  • pDC-plasmacytoid dendritic cells are best known as the rare and only immune cell that is specialized to produce type I interferons (IFNa and others). Immature pDC do not produce type I IFN, but when activated through either TLR7 or TLR9, they quickly switch into activated pDC, which secrete >99% of the IFNa made in response to infection and promote the most powerful cytolytic T cell responses that can be produced.
  • Immune-suppressing regulatory T cells, (Treg) and myeloid-derived suppressor cells (MDSC) are supported by immature tumor-infiltrating pDC.
  • CpG-A, the active ingredient in Checkmate’s drug, activates Toll-like receptor 9 (TLR9) in immature pDC. The resulting activated pDC secrete high concentrations of type I IFN such as IFNa with a complex mixture of Th1-inducing cytokines and chemokines into the tumor and draining lymph nodes after intratumoral injection. This represses Treg and MDSC, and attracts and activates other DC and anti-tumor T cells, generating the highest Th1 T cell responses reported (in mouse and human).
  • IFNa and the other Th1-promoting cytokines and chemokines secreted by the pDC mediate anti-tumor T cell responses by i) promoting conventional DC maturation and cross-presentation of tumor antigens to CD8+ T cells and ii) augmenting anti-tumor CD8+ T cell survival, expansion, and effector differentiation.

Learn how Checkmate's therapy can make checkpoint inhibitors work better


The immuno-oncology revolution

For decades, scientists and physicians knew that certain immune cells called Cytolytic T Lymphocytes (CTLs) are able to destroy cancer cells, yet they fail to play this key role for most patients suffering from cancer. Scientists and physicians now understand that tumors deploy “immune checkpoint proteins” to trick the CTLs to switch off before they can perform their cancer fighting role. The discovery of immune checkpoints led to the development of a new class of therapeutics, “checkpoint inhibitors,” that have ignited the immuno-oncology revolution.

Why do so few patients respond to checkpoint inhibitors?

Despite the promise of checkpoint inhibition, a limited number of patients currently benefit from this type of treatment. In a patient whose immune system is already activated and poised to kill their tumor, treatment with a checkpoint inhibitor can free the immune system to destroy the tumor (see example here). Unfortunately, most patients’ immune systems are not already activated so treatment with a checkpoint inhibitor does not provide any therapeutic benefit - and may actually worsen the patient’s condition by causing significant toxicity. In this case, the checkpoint inhibitor “takes the brakes off” the immune system, but fails to target it against the tumor, which continues to grow.

How can the response to checkpoint inhibitors be improved?

Many scientists believe that checkpoint inhibitors would have dramatically increased benefit if they were combined with an immune activator to stimulate the CTL attack against the tumor (for example, here). Many different immune activators have been tested and the Toll-like receptor 9 (TLR9) agonist CpG DNA has been the strongest at activating anti-tumor CTLs thus far. Checkmate Pharma believes that there is tremendous promise to the combination of two important cancer-fighting mechanisms: CpG DNA to activate the CTL response and checkpoint inhibition to release the tumor’s braking mechanism against the immune system. Checkmate’s founder and CEO, Dr. Art Krieg, discovered CpG DNA in 1994. Since then, CpG DNAs have been administered to thousands of humans showing potent immune activation and an excellent safety profile.

Tumors normally prevent T cell activation

CTLs have the potential to kill tumor cells but normally do not because they do not receive adequate levels of the three required stimulatory signals; and/or, they are arrested by “checkpoints” or inhibitory signals that turn them off (e.g. through PD-1 and CTLA-4). To be fully activated and kill tumor cells, CTLs must receive each of the three stimulatory signals from a dendritic cell (DC): 1) a tumor antigen must be “presented” to the T cell receptor (TCR); 2) “costimulation” must be provided through CD28 on the T cell; and 3) type I interferons (IFN) must stimulate the DC and T cells through the type I IFN receptor. However, tumors can evade the immune activation and proliferate by preventing the CTL response. Tumors recruit immature plasmacytoid DC (pDC) that provide only weaker, non-activating stimulatory signals (small “+” signs), and promote dominant inhibitory effects (larger “-“ signs) through the “checkpoint” molecules CTLA-4 and PD-L1. Thus successful tumors induce an environment in which the “-“ signals to CTLs dominate over the “+” signals needed to kill the tumors.

Tumor-associated pDC contribute to tolerizing tumor microenvironment

CpG activates plasmacytoid DC, inducing CTLs and tumor rejection in combination with anti-PD-1

Checkmate’s CpG DNA is the strongest stimulus known for pDCs, acting through the endosomal Toll-like receptor 9 (TLR9) to provide all three of the stimulatory signals (green “+” signs) required to induce a maximal anti-tumor CTL response. TLR9 signaling secondarily induces expression of the PD-1 checkpoint on T cells, which normally inhibits them. However, in the presence of a checkpoint inhibitor antibody to either PD-1 (shown) or to PD-L1, the fully activated T cells release cytolytic factors such as perforins and granzymes (granules in T cell) that act to effectively eliminate the tumor cells. Thus, combining a CpG DNA with a checkpoint inhibitor creates an environment with a dominant “+” effect, leading to tumor eradication by the CTLs.

TLR9 agonist CpG DNA activates pDC to drive T cell response with anti-PD-1

I want to read the primary scientific literature on pDCs


Review Articles

  1. Demoulin, Stéphanie, et al. "Tumor microenvironment converts plasmacytoid dendritic cells into immunosuppressive/tolerogenic cells: insight into the molecular mechanisms." Journal of leukocyte biology 93.3 (2013): 343-352.
  2. Di Domizio, Jeremy, Olivier Demaria, and Michel Gilliet. "Plasmacytoid dendritic cells in melanoma: can we revert bad into good?." Journal of Investigative Dermatology 134.7 (2014): 1797-1800.
  3. Lombardi, Vincent C., Svetlana F. Khaiboullina, and Albert A. Rizvanov. "Plasmacytoid dendritic cells, a role in neoplastic prevention and progression." European journal of clinical investigation 45 (2015): 1-8.

Basic science papers on the structural biology of CpG oligos, especially the unique effects of CpG-A and their polyG motifs on tumor-associated pDC

  1. Bates, Paula J., et al. "Antiproliferative activity of G-rich oligonucleotides correlates with protein binding." Journal of Biological Chemistry 274.37 (1999): 26369-26377.
  2. Zou, Weiping, et al. "Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells." Nature medicine 7.12 (2001): 1339-1346.
  3. Krug, Anne, et al. "Toll‐like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL‐12." European journal of immunology 31.10 (2001): 3026-3037.
  4. Shen, Weiyin, et al. "Antitumor mechanisms of oligodeoxynucleotides with CpG and polyG motifs in murine prostate cancer cells: decrease of NF-κ B and AP-1 binding activities and induction of apoptosis." Antisense and Nucleic Acid Drug Development 12.3 (2002): 155-164.
  5. Hartmann, Evelyn, et al. "Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer." Cancer research 63.19 (2003): 6478-6487.
  6. Rothenfusser, Simon, et al. "CpG-A and CpG-B oligonucleotides differentially enhance human peptide–specific primary and memory CD8+ T-cell responses in vitro." Blood 103.6 (2004): 2162-2169.
  7. Peng, Guangyong, et al. "Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function." Science 309.5739 (2005): 1380-1384.
  8. Labidi-Galy, Sana Intidhar, et al. "Quantitative and functional alterations of plasmacytoid dendritic cells contribute to immune tolerance in ovarian cancer." Cancer research 71.16 (2011): 5423-5434.
  9. Katsuda, Masahiro, et al. "Comparison of different classes of CpG-ODN in augmenting the generation of human epitope peptide-specific CTLs." International journal of oncology 39.5 (2011): 1295-1302.
  10. Sisirak, Vanja, et al. "Impaired IFN-α production by plasmacytoid dendritic cells favors regulatory T-cell expansion that may contribute to breast cancer progression." Cancer research 72.20 (2012): 5188-5197.
  11. Conrad, Curdin, et al. "Plasmacytoid dendritic cells promote immunosuppression in ovarian cancer via ICOS costimulation of Foxp3+ T-regulatory cells." Cancer research 72.20 (2012): 5240-5249.
  12. 1. Faget, Julien, et al. "ICOS-ligand expression on plasmacytoid dendritic cells supports breast cancer progression by promoting the accumulation of immunosuppressive CD4+ T cells." Cancer research 72.23 (2012): 6130-6141.

Our Team

Checkmate's team combines many decades of experience in all areas of drug development with a passion for innovation and execution.


Board of Directors

Oncology Advisory Board



For partnering and media inquiries please email the company at:

For other inquiries contact

  • Checkmate Pharmaceuticals
  • 1 Broadway, 14th floor
  • Cambridge, MA 02142