The Next Generation of Immunotherapy for Cancer: Small Molecules Could Make Big Waves

In 1891 the American surgeon W. Coley (1) reported that administration of a heat-killed bacterial vaccine (Coley toxins) could induce tumor regression in sarcoma patients, providing the first evidence that the immune system could be marshaled to treat cancer. Despite great strides in immunology and molecular biology, immunologists had been largely stymied in their efforts to develop robust and effective immune-based therapies for cancer. However, the last decade has brought significant successes that dispel any doubt that the human immune system can be harnessed to induce cancer regression and, in some patients, even long-term survival that for all intents and purposes represents a cure of their disease. The use of humanized mAbs that block the immune inhibitory receptors expressed by T cells and NK cells, like CTLA4 (ipilimumab/Keytruda; Bristol-Myers Squibb [BMS]) or PD-1 (nivolumab/Opvido, BMS; pembrolizumab/Keytruda, Merck), has proved to be an effective cancer therapy in metastatic melanoma, lung cancer, and kidney cancer (2). Genentech/Merck have also developed a blocking Ab for the PD-1 ligand PD-L1 (atezolizumab/Tecentriq) that has been approved for use in bladder cancer (3) and in lung cancer when patients have failed chemotherapy. Chimeric Ag receptor–transduced T (CAR-T) cell grafts that redirect T cell immunity to CD19 have also been proved to be a highly effective therapy for pediatric pre–B ALL (4). Clinical success has also been demonstrated with a dendritic cell (DC)–based vaccine for prostate cancer (PROVENGE; Dendreon), which would undoubtedly have pleased both Coley and R. Steinman, who discovered DCs (5). These advances were made possible by a variety of fundamental advances in molecular and cellular immunology made in the last 50 years that serve as a resounding proof that basic scientific research can lead to effective therapies for diseases once considered incurable.

The foundation for the pursuit of small molecule immune therapies for cancer is the wide spectrum of cells and their molecular pathways that are used by the immune system to suppress or enhance cellular immunity. Such novel immunotherapeutic approaches can either negate immune suppression in the tumor milieu or facilitate cytolytic lymphocyte responses to the tumor. In both contexts, the quality and/or the quantity of tumor-reactive cytotoxic T cells is increased, resulting in improved tumor regression. These approaches can facilitate the initial priming of T cells that can recognize tumor-specific neoantigens or, alternatively, abrogate immune suppressive mechanisms in the tumor that hamper cytolytic lymphocytes. Agents that target receptors that restrain cytolytic lymphocytes are commonly referred to as immune checkpoint inhibitors (ICI). For example, Ab blockade of the immune checkpoint receptor CTLA-4 is thought to enhance tumor immunity by enabling the initial priming of tumor-reactive T cells, whereas PD-1 blockade is thought to relieve suppressive mechanisms that contribute to exhaustion of CD8⁺ T cells present in the tumor milieu. The success of ICI approaches for both PD-1 and CTLA-4 demonstrates that either strategy can lead to effective immune control of tumors with improved survival of patients (2). Despite their obvious and impressive successes, there are still limitations associated with these new immuno-oncology treatments. Protein-based ICI approaches have shown significant toxicity, including immune attack on the gastrointestinal tract and lungs in a significant percentage of patients. In some cases, these autoimmune attacks can be lethal. In addition, ICI appear to only be effective in “hot” tumors that are rapidly growing and not in slower-developing cold tumors, in which there is a lower frequency of mutations in the tumor and, thus, a lower probability that there are tumor-specific neoantigens for T cells to recognize and target.

Alternatively, CAR-T cells use a gene therapy approach to improve the number of T cells that can respond to cancer cells. The tremendous success of CAR-T cells in targeting CD19⁺ pre–B ALL may be difficult to replicate with solid tumors of epithelial origin, in which there may be a lack of extracellular Ags that can be targeted by a CAR without also targeting normal epithelial tissues that are necessary for host survival. This poses a significant challenge for generalization of the CAR-T cell strategy to cancers beyond hematologic malignancies (6).

For immunotherapy to make further strides in the treatment of cancer, novel approaches are very much needed. Both stand-alone therapies to improve the quality of the immune response to cancer and combination modalities that can further enhance already successful agents are under active investigation. In parallel to the clinical advances made by ICI and CAR-T cells, a wave of small molecule–based immune therapies have been proceeding from initial discovery to clinical testing (see Fig. 1, Table I). Among these are compounds that can target immune suppressive mechanisms or activate pathways in innate and/or adaptive immune cells that biologic therapies are not capable of accessing. Additional advantages of small molecules over biologics include oral bioavailability, greater penetration of the tumor milieu, and the ability to cross cell membranes to access intracellular targets. Small molecules are also more amenable to fine control of their bioavailability, which may enable them to avoid some of the immune-associated adverse events associated with Ab- and cell-based biologic therapies. Another key advantage of small molecules is their lower cost to produce and administer, which could enable greater patient access than is feasible with biologic therapies, especially in the developing world (7, 8). The diverse types of immune cells, receptors, and molecular pathways implicated in responding to the tumor or in suppressing these responses offers a cornucopia of potential molecular targets. Interrogating these systems via pharmacologic intervention has become the focus of numerous small molecule immunotherapeutic development programs. In general, these molecular targets correspond either to receptors or to enzymes involved in intracellular signal transduction.

Tumor cells and immune suppressive myeloid cells in the tumor microenvironment can express the ligand for PD-1, PD-L1. When PD-L1 engages PD-1, this triggers exhaustion of CD8⁺ cytotoxic T cells that have entered the tumor, compromising the tumor-reactive cytolytic T cell response. Many mAb therapies target the PD-1–PD-L1 axis, disrupting this interaction and, thus, increasing the T cell response to the tumor. However, these therapeutics can also promote an immune attack on normal tissues, including the gastrointestinal tract, lung, and thyroid, and thus immune-related adverse events occur at a significant frequency and, in some patients, with severe and sometimes fatal consequences (9). The extended in vivo t_1/2 of humanized Ab therapeutics has been implicated in contributing to these toxicities (8). Small molecule approaches that antagonize the PD-1–PD-L1 interaction are now sought, as these may prove more amenable to control of their bioavailability, which may alleviate toxic side effects. Thus, to build on the proven success of ICI, there has been significant effort to develop small molecule antagonists for the ICI receptor PD-1. Initial approaches focused on the use of peptides or peptidomimetics that antagonize the PD-1–PD-L1 interaction. These initial leads have further evolved to more conventional small molecules that successfully antagonize PD-1–PD-L1 binding (8). The most recent iteration in this molecular evolution are the substituted biaryl-derivatives generated by scientists at BMS (10). The best two compounds that emerged from this program, BMS-1001 and BMS-1116, can completely restore anti-CD3–mediated T cell activation in a Jurkat T cell line transfected with an NFAT-luciferase reporter construct (11).

Recently, the biopharmaceutical company Curis reported two small molecules that not only antagonize PD-L1 binding but also bind to the other ICI, VISTA (CA-170) or TIM-3 (CA-327). CA-170 has advanced to phase I clinical testing in patients with advanced cancer (12). These compounds offer the exciting possibility of simultaneously antagonizing multiple ICI receptors, which may be more efficacious as this approach could prevent immune escape by tumor types that can upregulate a single immune checkpoint receptor ligand in response to monotherapy. Recent clinical results in which different anti–CTLA-4 and anti–PD-1 mAb monotherapies were combined to improve patient responses suggest that small molecules that can block more than one ICI receptor could have considerable success (13). Small molecules that effectively antagonize ligand binding to an ICI receptor and exhibit potent activity in cell-based assays suggest that this immunotherapy tactic holds significant promise, particularly if greater control of their pharmacodynamics and pharmacokinetics can avoid the immune-associated adverse events associated with ICI mAbs. These approaches may also lead to the development of small molecule ICI approaches that can penetrate the blood–brain barrier, enabling ICI to be applied to primary brain cancer or brain metastases that are not amenable to treatment with current Ab-based ICI therapies (14).

Agonists of pattern recognition receptors are also being pursued as potential immunotherapies or adjuvants to prime responses following tumor cell vaccination (2). These agonists are grouped into two general categories: nucleotide oligomerization domain (NOD)–like receptor (NLR) agonists and TLR agonists. Agonists of TLR have garnered the most attention in this area. There are a total of 13 TLRs, and they are expressed across a broad spectrum of immune cells, including DCs, B cells, macrophages, NK cells, and T cells. Because TLRs can promote T cell responses against tumors, their agonists are being pursued in immuno-oncology (15). The best-characterized compounds to date are the imidazoquinolines such as imiquimod and derivatives thereof. These compounds serve as TLR7/8 agonists. The parent compound, imiquimod, has already been approved for topical use in basal cell carcinoma (8). Trials in metastatic melanoma and localized bladder cancer are also being pursued, with positive results being obtained in the latter (16, 17). The imiquimod analog resiquimod has also been used topically in cutaneous T cell lymphoma with initial positive results (18). However, one of the main limitations in this area is the potentially severe toxicity associated with systemic administration of TLR7/8 agonists, as they can trigger a serious cytokine storm that has the potential to be lethal. This has limited their clinical utility (8). To overcome this drawback, new TLR7 (852A) and TLR8 agonists (852A and VTX-2337) have been developed. These molecules are optimized for systemic delivery to avoid toxicity. These compounds have been tested in patients with hematologic cancers and solid tumors with objective responses by their tumors to the treatment observed (19–23). Although there appears to be promise for TLR agonists in immuno-oncology, Huck and coworkers (24) have cautioned that sustained TLR-induced immunity can, in some contexts, promote cancer growth and, in some instances, also promote immunosuppressive cell increases. Thus, further research is required to better understand what agonists to use and also how they should be dosed and delivered for maximum effect while avoiding these negative effects.

Another immunostimulatory small molecule molecular target is the stimulator of IFN genes (STING) signaling pathway, which is expressed by epithelial cells, endothelial cells, and immune cells such as DCs and T cells. When tumor cells undergo necrosis, they release DNA that, when taken up by DCs, is detected by the cyclic-GMP-AMP synthase (cGAS). cGAS then produces cGAMP, which binds to and activates STING in the endoplasmic reticulum. STING activation leads to nuclear translocation of transcription factors that induce expression of IFNs and cytokines, promoting recruitment and activation of T cells, thereby mediating tumor control (25, 26). The STING pathway can also be activated by synthetic cyclic dinucleotides (CDNs) like 2′,3′-cGAMP. Recently, phosphothioate derivatives of CDNs that are resistant to mammalian phospho-diesterases have been developed as STING agonists that have increased stability in vivo (27, 28). Several synthetic CDNs, or indirect small molecule modulators of the pathway, are being tested clinically as vaccine adjuvants or in combination with ICI therapies (e.g., ADU-S100, MK-1454) (29). One limitation for CDNs is that current versions must be directly injected into tumors (24). It is unclear whether systemic administration of these potent immune stimulants can be done safely, as many of the same concerns that apply to TLR agonists are also an issue for STING agonists. To address this concern, covalent STING inhibitors have recently been identified that can reduce inflammatory cytokines induced by STING agonists (30). A STING inhibitor could be used as a pharmaceutical “kill switch” in the event that systemic STING agonist administration triggers adverse immune events in a patient.

The Tek family kinases Bruton tyrosine kinase (Btk) and inducible T cell kinase (Itk) play crucial roles in immune cell signaling. Btk is critical for not only BCR signaling but also myeloid cell activation, whereas Itk plays a role in proximal TCR signaling that promotes Th2 immunity. In addition, studies with Itk^−/− mice indicate that Itk is essential for regulatory T (Treg) cell differentiation mediated by the transcription factor IRF4 (31). This turns out to be crucial for tumor immunity, as the irreversible covalent inhibitor of both Btk and Itk, ibrutinib, can compromise Th2 immunity, thereby creating a Th1-biased T cell compartment that favors cellular immunity to certain pathogens and tumor cells (32). If ibrutinib can also simultaneously reduce Treg cell numbers in the tumor milieu, as suggested by August and colleagues (31), then an unbridled antitumor Th1 response would likely occur. In a separate study, ibrutinib was found to not only enhance in vivo eradication of lymphoma tumors that express Btk when combined with PD-1/PD-L1 blockade but was also effective in breast and colon carcinomas that lack expression of either Itk or Btk (33). Efficacy in these latter epithelial tumor models demonstrates that ibrutinib has antitumor effects independent of its chemotherapeutic effect by enhancing tumor immunity, at least when combined with ICI. When ibrutinib and the Btk-selective inhibitor acalabrutinib were compared directly in chronic lymphocytic leukemia (CLL) patients, ibrutinib was found to have a much more potent effect on increasing CD8⁺ T cell numbers, suggesting the tumor-promoting target of these compounds is via inhibition of the Tek kinase Itk expressed by T cells (34). Multiple clinical trials are currently underway in which either ibrutinib or acalabrutinib is being paired with Ab ICI therapies, and thus information regarding the effectiveness of Btk and/or Itk inhibition for cancer immunotherapy should soon be forthcoming (35, 36). However, the current preclinical and clinical findings suggest that more potent and selective Itk inhibitors may also find a role in immuno-oncology.

Like Btk and Itk, SHIP1 has also recently emerged as a chemo-immunotherapeutic target. The anticancer properties of SHIP inhibitors were first demonstrated in hematolymphoid cancers, such as multiple myeloma (MM) and acute myelogenous leukemia, in which SHIP1 surprisingly promotes the survival of cancer cells through the production of PI(3,4)P₂ (37, 38). Although the direct product of PI3K, PI(3,4,5)P₃, is well known to promote activation of Akt, it was also found that the SHIP1 product PI(3,4)P₂ can recruit and promote robust activation of Akt at the plasma membrane (39, 40). Consequently, treatment of cells with a SHIP1-selective inhibitor 3AC promotes cell death in hematologic cancers by limiting production of PI(3,4)P₂ and activation of Akt (37, 38), although in B and T cell lymphomas, 3AC can also induce extrinsic cell death as SHIP1 is recruited to CD95/Fas in these cells to limit activation of Caspase 8 (41). Hence, 3AC monotherapy was found to promote long-term survival in MM-challenged NSG mice (38), demonstrating the chemotherapeutic potential of SHIP1 inhibition. Pan-SHIP1/2 inhibitors like K118 and K149 can also promote apoptosis in SHIP2-dependent breast and colon cancer cells (38, 42). This also appears to be because these compounds deprive the epithelial cancer cells of PI(3,4)P₂ produced by SHIP2 (38, 42). These findings suggest that both PI(3,4,5)P₃ and PI(3,4)P₂ are required to maintain the survival of malignant cells—the “Two PIP Hypothesis” (43). Both the SHIP1-selective inhibitor 3AC and the pan-SHIP1/2 inhibitors K118 and K149 have a variety of activities in vivo, including the ability to expand and mobilize hematopoietic stem cells (44), reverse obesity (45), and promote engraftment of both autologous and allogeneic hematopoietic stem/progenitor grafts (46). These studies established that SHIP inhibition has significant therapeutic potential without apparent limiting toxicities (47). Initially, there was little consideration that such compounds might promote tumor immunity, as extended daily treatment with SHIP1-selective 3AC was found to disarm NK cells, compromising MHC-mismatched bone marrow graft rejection, and also promoted expansion of immunoregulatory myeloid-derived suppressor cells (MDSC) and Treg cell compartments in vivo, all of which could potentially contribute to compromised immune control of tumors (46). However, it was subsequently shown that a shorter duration of SHIP1 inhibition, given in a pulsatile manner, neither disarmed nor exhausted NK cells or T cells and, in fact, enhanced their activation, resulting in long-term survival in lymphoma-challenged mice treated with pulsatile, short-duration doses of 3AC (48). Dramatic antitumor responses were also observed in 3AC-treated mice challenged with two different colon cancers that do not express SHIP1 (48), demonstrating that SHIP inhibition has potent antitumor effects independent of its chemotherapeutic activity. Interestingly, neither pan-SHIP1/2 inhibitor, K118 or K149, was able to promote antitumor immunity in the lymphoma model. In fact, when lymphoma-challenged mice were cotreated with a SHIP2-selective inhibitor, AS1949490 (49), and the SHIP1-selective inhibitor 3AC, extension of host survival by 3AC was completely abrogated, demonstrating that SHIP1 selectivity is essential for this small molecule immunotherapeutic approach. This preclinical study with the first SHIP1-selective inhibitor suggests there is potential for SHIP1-selective compounds in immuno-oncology.

The last decade has brought significant advances in our ability to selectively inhibit the major isoforms of PI3K, with some of these inhibitors (e.g., idelalisib) advancing to clinical testing as chemotherapies in a variety of cancers, including B lymphoid cancers and breast cancer. Two PI3K isoforms, PI3K-γ and PI3K-δ, are expressed only in the hematolymphoid compartment, and thus their use has been explored in hematologic malignancies. PI3K-δ plays a major role in B cell signaling and is frequently overexpressed in B cell lymphomas. This has led to clinical testing of the PI3K-δ inhibitor idelalisib in B cell neoplasms and subsequent Food and Drug Administration approval for treatment of various B cell malignancies, including CLL, follicular lymphoma, and small lymphocytic lymphoma (24, 50). The use of PI3K-δ inhibitors to boost the immune response in cancer also garnered attention, with PI3K-δ inactivation improving T cell control of tumor growth in vivo (51, 52). A clinical trial to test the combination of idelalisib with pembrolizumab in patients with CLL or B cell lymphoma is currently recruiting (53). However, a recent report using tumor-challenged PI3K-δ–mutant mice indicates that PI3K-δ inhibition could actually compromise ICI (54). A final verdict will likely be rendered with the results of the clinical study, as genetic inactivation of a target, which is both complete and permanent, does not necessarily have the same physiological outcome as small molecule inhibition. The PI3K-γ isoform has also been implicated as being essential in control of tumor immunity. Both genetic mutation and chemical inhibition in vivo indicate that PI3K-γ promotes polarization of tumor-associated macrophages to an M2/AAM phenotype that, through expression of Arginase1 and immune checkpoint receptor ligands, can suppress CD8⁺ T cell responses in the tumor (55). In this study, PI3K-γ inhibition with the orally bioavailable, selective PI3K-γ inhibitor IPI-549 improved the antitumor efficacy of an anti-PD-1 Ab. IPI-549 is currently undergoing clinical testing in combination with nivoluminab against different cancer types (56, 57).

The enzymatic pathways leading to the production of N-formyl-kynurenine, a potent inhibitor of T cell activation, have also been the subject of a great deal of study over the last decade. This resulted from the initial observations of Van den Eynde and coworkers (58), who showed that tumor cells express IDO, a heme-containing dioxygenase, and that its catabolism of tryptophan along with other enzymes in the pathway (TDO, IDO2) to yield kynurenine helps tumor cells evade immune detection. Kynurenine has a variety of immunosuppressive effects in the tumor microenvironment that include depriving effector T cells of tryptophan required for TCR activation, promoting Treg cell function through the aryl hydrocarbon receptor (AHR), and antagonizing CD8 T effector function by inducing PD-1 expression subsequent to activation of AHR (7, 59). Thus, IDO inhibition or other components of the tryptophan catabolism pathway have been the subject of intensive efforts in immuno-oncology, with some potent IDO inhibitors (e.g., epacadostat) advancing to phase III clinical trials in combination with Ab therapies. However, recent clinical results have been disappointing, leading to a rapid retrenchment by pharmaceutical firms active in this area, despite significant prior investment (60). What the future holds for IDO inhibitors or enzymes in the pathway in immuno-oncology is difficult to predict, but given the broad retreat by major pharma, concerns over the future of this area appear justified.

The inhibition of arginine catabolism is also viewed as a potential approach to relieve immune suppression in the tumor milieu. This is due to the fact that the immunosuppressive myeloid cell population, like MDSC and tumor-associated macrophages, expresses Arginase1, an enzyme that breaks down the amino acid arginine into ornithine and urea. Arginine is required for expression of the CD3ζ chain in the TCR complex, and thus extracellular depletion by Arginase1 in the tumor milieu compromises T cell effector function at the tumor site (61). An additional mechanism of action for Arginase inhibitors involves depletion of arginine, which may trigger a substrate switch by iNOS, stimulating the production of reactive oxygen and nitrogen species, which could also promote immune suppression. Thus, dual inhibition of both Argininase1 and iNOS might be a preferred therapeutic path (7). A nitrooxy aspirin analog, NCX-4016, has been shown to have such an inhibitory profile and to improve immune responses to tumors in vivo (62). Subsequent research led to the identification of a more potent compound, the salicylate AT-38, that also demonstrated antitumor activity in vivo (63). To date, there does not appear to be a clinical development program devoted to this class of compounds in immunotherapy, perhaps owing to effects on key physiological processes, such as vascular function.

Catabolism of ATP can also mediate immune suppression in the tumor microenvironment. ATP is interpreted as a danger signal by the immune system through its ability to activate the NLRP3 inflammasome in DCs, leading to secretion of IL1-β, which further promotes the inflammatory response in infection and cancer. However, in the tumor microenvironment, Treg cells express extracellular ectonucleotidases (CD73, CD39) that dephosphorylate ATP to yield adenosine (64). Adenosine binds to adenosine A2A and A2B receptors on lymphocytes in the tumor and suppresses their ability to mediate antitumor effector functions, such as cytolysis. Adenosine can also amplify the immunosuppressive effects of Treg cells by binding to the A2A receptor on their surface (65). A hypoxia–adenosinergic axis is proposed in the tumor microenvironment, where the hypoxia-inducible transcription factor α (HIF-1α) can activate several of the above receptors that contribute to immune suppression in the tumor (7). Thus, small molecules that target either the ectonucleotidases (CD39, CD73) or the adenosine receptors (A2A or A2B) could serve as potential therapeutics to reduce the immunosuppressive milieu present in tumors. Toward that end, antagonists of the A2A receptor (e.g., CPI-444) or its genetic inactivation have been shown to promote robust antitumor CD8⁺ T cell responses in a weakly immunogenic sarcoma model and improve ICI responses in other murine tumor models (66, 67). Consequently, several A2A antagonists that were initially explored as therapeutics for Parkinson disease have now been repurposed for immunotherapy and are being tested clinically, either as single agents or in combination with ICI therapies. These include vipadenant (68), SCH 420815 (preladenant) (69), PBF 509 (70), AZD4635 (71), and CPI-444. Initial clinical results have recently been reported for CPI-444, in which it was found to have antitumor activity both alone and in combination with anti–PD-L1 in multiple tumor types (24). Thus, there is reason for optimism that A2A agonists can restore the CD8⁺ T cell response in patients to improve the immune control of tumor growth. Indeed, A2A is currently perceived to be the highest-value molecular target in the hypoxia–adenosinergic axis that contributes to immune suppression.

TGF-β signaling is known to promote immune suppression, not only in the tumor microenvironment but also systemically, where it can compromise immune surveillance. Consistent with TGF-β signaling promoting potent immune suppression, pharmacological inhibition of the TGF-βR1 kinase/Alk5 triggers immune activation and synergy with immune therapies (72–74). Thus, the TGF-βR1 kinase/Alk5 inhibitor galuniseritib is currently being tested clinically in combination with an anti–PD-L1 therapy (durvalumab) in pancreatic cancer (57).

An emerging approach for small molecule–based immunotherapy is the potential use of CBP/EP300 bromodomain inhibitors. Bromodomains enable transcription factors and proteins that regulate epigenetic marks to bind selectively to acetylated histones and, in so doing, alter the chromatin accessibility of genes. Small molecule CBP/EP300 bromodomain inhibitors have recently been identified (75–77). These inhibitors have been shown to have two key activities that could potentially make them useful for increasing the response of cytolytic NK cells and T cells in the tumor microenvironment. CBP/EP300 bromodomain inhibitors have been shown to decrease acetylation of FOXP3, which increases its degradation, thus compromising Treg cell function (75). Alternatively, CBP/EP300 bromodomain inhibition can upregulate expression of MICA, an NKG2D ligand, on human MM cells. This should make MM cells better at activating both NK cells and CD8⁺ T cells in the immune response to cancer cells (78). Therefore, CBP/EP300 bromodomain inhibition approaches may be able to reduce Treg cell function in tumors in vivo, while simultaneously making tumor cells more visible to NKG2D-expressing subsets of NK cells and CD8⁺ T cells. This would represent a significant advance for small molecule approaches for tumor immunotherapy.

Over the last decade it has been appreciated that certain chemotherapies can cause the death of cancer cells in a manner that facilitates tumor Ag presentation to T cells, and thus these chemotherapies not only directly kill cancer cells but also enhance immunogenicity of the tumor. This phenomenon is referred to as immunogenic cell death and appears to be due at least in part to calreticulin presentation of tumor Ags (79). In general, however, chemotherapies that enhance the immune response appear to facilitate mutations and, thus, the generation of tumor-specific neoantigens. In addition, they also promote tumor release of danger or stress signals that act as adjuvants for the tumor-specific immune response (80). Because they increase the antigenicity and adjuvanticity of the tumor, such chemotherapies can have a wide array of effects on the immune system that may also facilitate the antitumor response. However, it should also be recognized that these chemotherapies can also have potent immune suppressive effects. Nonetheless, some chemotherapeutic compounds exert direct effects on the immune compartment that, in some cases, might have an overall immune-promoting effect. For instance, tyrosine kinase inhibition of VEGF signaling by dasatinib, sunitinib, or sorafenib can suppress both Treg cell and MDSC numbers and function. For a comprehensive review of chemotherapeutics that can also impact the immune response to the tumor, the reader is referred elsewhere (81).

This brief review has hopefully engendered enthusiasm for the development of small molecule–based immune therapies for cancer. Based on the wide array of small molecule immunotherapies currently proceeding through the development continuum from discovery to clinical testing, there is reason for optimism. Like their biological predecessors, these therapies can either abrogate immune suppression that hampers immune responses to the tumor or promote more effective cytotoxic lymphocyte responses to the tumor. Small molecule approaches offer inherent advantages over biologic immunotherapies because they can access a wider spectrum of molecular targets, including those that are intracellular or those deep in the tumor milieu. In addition, small molecules offer more control over dosing than biologics, which may aid in reducing immune-related adverse events seen with biologic therapies. An important consideration for the future development of small molecule–based immune therapies is also a socioeconomic one. Small molecule therapies, because of their lower production and development costs, should offer greater patient access to advanced immunotherapy, regardless of wealth or nationality. It remains to be determined if these therapies will prove effective in cancer patients as monotherapies, in combination with biologics, or in combination with traditional cancer therapies like chemo- and radiotherapy. However, given the wide spectrum of targets that can be pursued in this arena and the previous successes of small molecule therapies for cancer, there is reason for cautious optimism.

W.G.K. is Chief Scientific Officer of Alterna Therapeutics, a company devoted to commercializing inhibitors of SHIP1 and SHIP2. J.D.C. serves on the Scientific Advisory Board of Alterna Therapeutics. Both W.G.K. and J.D.C. have patents issued and pending concerning the inhibition of SHIP1 for therapeutic purposes.