Small-Molecule Targets in Immuno-Oncology

Abstract

Advances in understanding the role and molecular mechanisms underlying immune surveillance and control of (pre)malignancies is revolutionizing clinical practice in the treatment of cancer. Presently, multiple biologic drugs targeting the immune checkpoint proteins PD(L)1 or CTLA4 have been approved and/or are in advanced stages of clinical development for many cancers. In addition, combination therapy with these agents and other immunomodulators is being intensively explored with the aim of improving primary response rates or prolonging overall survival. The effectiveness of cancer immunotherapy with biologics is spurring research in alternate approaches including small-molecule-mediated targeting of intracellular pathways modulating the innate and adaptive immune response. This focus of this review is on some of the key intracellular pathways where the development of a small-molecule therapeutic is attractive, tractable, and potentially synergistic with extracellular biologic-mediated immune checkpoint blockade.

Recent updates on cancer immunotherapy

“…antibodies, CAR T), because they can (i) target intracellular pathways, (ii) induce acute anti-tumor effects and avoid systemic immunogenicity, thereby improving therapeutic index, (iii) easily penetrate solid tumors, (iv) be orally administered allowing flexible dosing, and (v) be cost-effective. 86,87…”

HTiP: High-Throughput Immunomodulator Phenotypic Screening Platform to Reveal IAP Antagonists as Anti-cancer Immune Enhancers

“…To complement and potentially synergize with the immunotherapeutic antibodies and engineered immune cells, alternative therapeutic agents such as small-molecule immunomodulators remain to be developed (Dhanak et al, 2017). Small molecules offer a number of advantages, including improved bioavailability, enhanced tissue penetration, and the capability to reach intracellular targets of both immune and cancer cells.…”

“…Moreover, small molecules could also serve as chemical probes for investigating mechanisms involved in anti-tumor immunity. Although there is an emerging effort in target-based screenings to identify small molecules that modulate a specific protein target (Dhanak et al, 2017;Huxley et al, 2004;Skalniak et al, 2017), phenotypic screenings reflecting the complex immune response network for large-scale high-throughput small-molecule immunomodulator discovery are highly challenging and remain to be established.…”

Discovering Anti-cancer Immune Enhancers in a Miniaturized Immune-Tumor Microenvironment

“…Six of the ten top-selling drugs of 2017 were monoclonal antibodies (Urquhart, 2018), and new immunotherapy products are constantly being developed, including recombinant proteins, antibodies, and cytotherapies. However, although impressive results have been achieved with immunotherapies for some diseases, such as melanoma, these treatments are largely ineffective for many other conditions, such as colorectal cancer (Boland and Ma, 2017;Dhanak et al, 2017). Therefore, new treatments with different compositions and mechanisms of action are highly desirable for use as monotherapies or in combination with other modalities.…”

“…Furthermore, biologics must be administered by injection, adding not only to shipping and storage costs, but also to patient discomfort. Small-molecule immunomodulators have a clear place in the modern era of immunotherapies by offering several advantages over biologics, including potentially lower cost, suitability for oral administration, improved bioavailability and tissue penetration, and the potential to reach intracel-lular targets that biologics currently cannot reach (Cheng et al, 2018;Dhanak et al, 2017). Discovery efforts in this area are hindered, however, by a lack of relevant in vitro cell culture methods that recapitulate the complex cellular milieu present in vivo, and this issue is further compounded by the level of miniaturization necessary for high-throughput screening.…”