Q&A: Small molecules and the cancer landscape

Small molecules are a mainstay in pharmaceutical therapeutics and cancer is a longstanding disease area that has captured much of the attention in pharma and biotech R&D. We talked recently with Aduro Biotech’s chief scientific officer, Dr. Thomas Dubensky, about both and about other related issues in the oncology landscape, including the STING pathway.

Thomas Dubensky: Small-molecule therapeutics have been the bastion of oncology therapeutics for decades. More recently, precision approaches targeting signaling/cell growth pathways that are dysregulated through mutation—such as the BRAF inhibitor vemurafenib developed by Plexxikon—that target a particular mutation that is prevalent in melanoma, have been approved. With the emergence of immuno-oncology (IO) as a therapeutic area, multiple groups are focused on the development of small molecules that target, for example, innate immune receptors as well as immune checkpoints.

Dubensky: Vemurafenib was approved for advanced melanoma due to its specificity for a common mutation (V600E) in this cancer and for its high response rates. However, due to the high relapse rates, this therapy is now commonly combined with small-molecule drugs that inhibit the MAP kinase pathway. Several small-molecules drugs that activate the innate immune system are in clinical development. One such example is a small molecule known as VTX-2337 (Motolimid) developed by VentiRx and licensed by Celgene, which activates innate immunity through TLR8 and is being evaluated in several clinical trials, alone and in combination with immune checkpoint inhibitors.

Dubensky: Recent reports have provided the mechanistic insight of how innate immune activation promotes priming of antitumor immunity and informs the development of clinical approaches to facilitate this process. Spontaneous T cell infiltration of melanoma lesions in humans is correlated with a type I interferon (IFN) transcriptional profile in the tumor microenvironment (TME) and infiltration of lymphocytes, indicative of ongoing innate immune recognition within the tumor. Substantial evidence indicates that tumor infiltrating lymphocytes (TILs), including activated CD8⁺ T cells, is predictive of a positive clinical outcome in response to several immunotherapy strategies.

Similarly, in mice bearing melanoma, there is a correlation between expression of IFN-β by tumor-resident dendritic cells (DCs), and spontaneous priming of tumor-specific immunity. Induction of IFN-β expression and co-regulated IFN-responsive genes and pro-inflammatory chemokines is dependent upon activation of the STING (stimulator of interferon genes) pathway, mediated through sensing of tumor dsDNA in TME-resident dendritic cells by cyclic GMP-AMP (cGAMP) synthase (cGAS), which in turn synthesizes cGAMP.

The cyclic dinucleotide (CDN) cGAMP produced by cGAS is the natural STING agonist ligand. Thus, the cGAS-STING signaling axis has emerged as a central node for sensing damage in the host. We posited recently in Cell Reports (Corrales et. al., 2015) that direct activation of the STING receptor in the TME by intratumoral (IT) injection of specific CDNs was an effective therapeutic strategy to promote broad tumor-initiated T cell priming against an individual’s tumor antigen repertoire. In the Cell Reports publication, we demonstrated that direct engagement of STING through IT administration of the synthetic highly active CDN derivative developed by Aduro, known as ADU-S100, results in effective antitumor therapy and long-term survival in various mouse syngeneic tumor models. IT injection of ADU-S100 also generates substantial systemic immune responses capable of rejecting distant metastases and provided long-lived immunologic memory. The safety, tolerability and possible antitumor response of ADU-S100 is now being evaluated in a Phase 1 clinical trial in multiple sites in the U.S. among patients with advanced cutaneously accessible cancers that are refractory to standard-of-care therapies.

Dubensky: The notion of intratumoral delivery to activate the TME locally is based on the concept that the tumor itself can serve as a “vaccine” for a patient having metastatic cancer. An immune response initiated (primed) locally in the treated (injected) tumor results in a tumor-specific cellular (T cell) immune response that is systemically active and these T cells can traffic to and kill distal non-injected metastases. This therapeutic strategy has garnered strong interest in the IO field because it is appreciated that direct activation of the STING pathway through IT injection results in the priming of a T cell response that is specific to an individuals’ unique tumor antigen repertoire—essentially an approach where ADU-S100 is an off-the-shelf small molecule yet stimulates a broad immune response that is patient specific. This is a different paradigm from cancer vaccines, which are principally recombinant vectors or adjuvanted proteins/peptides that are designed to stimulate an immune response to tumor-associated antigens that are commonly shared among a targeted cancer.

Dubensky: It is generally accepted in the field that immunotherapy is most effective in the setting of minimal residual disease, such as that what results post-surgery and/or standard of care chemo/radiotherapy. Again, the therapeutic intent of localized cancer immunotherapy is to use an accessible tumor mass(es) as a “patient-specific” vaccine, whereby direct activation of the STING pathway in the tumor leads to local priming of a T cell response that is specific for critical rejection antigens that is then systemically active.

Dubensky: Aduro is advancing its three of proprietary platforms LADD, STING and B-Select in several ongoing and planned clinical trials. Since these platforms can be used to activate both the innate and adaptive arms of the immune system as well as to sustain its activity through blocking of negative immune checkpoint pathways (e.g., CTLA-4 and PD-1), the company expects to rationally combine these agents in future clinical studies.

Dubensky: We are very excited about our diverse and broad product pipeline moving forward in development for a wide variety of cancers. Importantly, our immunotherapy platforms may apply to more than just cancer, with applications in infectious and other diseases. We remain focused on bringing safe, effective therapies to the patients in need, and it’s the patients that motivate each of us at Aduro Biotech to work hard each day.

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Thomas W. Dubensky Jr., Ph.D., has served as Aduro’s chief scientific officer since September 2011. From 2009 to 2011, Dubensky served as chief scientific officer of Immune Design Corp., a biotechnology company, where he was responsible for overseeing the development of immune therapies based on proprietary molecularly defined adjuvants and dendritic cell-targeting vaccine platforms. He was a co-founder and chief scientific officer of Anza Therapeutics Inc., a biotechnology company which was spun out from Cerus Corp. in 2007, where he served as the vice president of research beginning in 2002.