Cancer Immunotherapy Targeting T Cell Costimulatory Molecules

According to the American Cancer Society, over 1.5 million new cancer cases will be diagnosed this year, a figure that is expected to rise with the aging population. Chemotherapy and radiation are the current "gold standards" for cancer treatment, but these therapies are marginally effective, toxic, and serve to diminish the quality of life for cancer patients. Immunotherapy represents an attractive alternative to these traditional treatment regimens. Despite overwhelming evidence that the immune system is capable of recognizing and eliminating tumors, both spontaneously and in response to immune-based therapy, such protection is abrogated in the face of compensatory immunosuppressive events characteristic of progressive disease. Thus, a major goal of novel immune-based therapies is the coordinate silencing of regulatory circuits and amplification of protective T cell function.While immune modulating reagents that trigger the T cell costimulatory molecules OX40 and GITR are currently being evaluated in early-phase clinical trials, little pre-clinical information is available regarding the efficacy and mechanism(s) of action for these agents in the setting of advanced, well-established disease. To further characterize the molecular, cellular, and treatment-associated consequences of OX40 and GITR engagement, novel agonistic reagents directed against murine OX40 and GITR (ligand-Fc fusion proteins) were recently constructed and characterized in vitro. We now show that the growth of well-established, day 17 sarcomas is significantly inhibited or ablated by a short course of either treatment, with OX40L-Fc demonstrating superior anti-tumor efficacy over GITRL-Fc at comparable dosing. Both treatments were capable of eliminating regulatory T cells within tumors, inducing profound proliferation of T effector cells in the tumor-draining lymph node, and promoting the recruitment of these expanded effector cells to the tumor microenvironment. However, OX40L-Fc therapy mediated additional, T cell-independent effects, including the activation of tumor-localized dendritic and endothelial cell subsets. These changes rendered the tumor microenvironment more immunogenic and permissive to the infiltration of treatment-induced, protective immune cells. The pleiotropic anti-tumor effects demonstrated in this model by OX40L-Fc, and to a lesser extent GITRL-Fc, strongly supports the further translation of such modalities into human clinical trials, either as single agents or in the context of combinational immunotherapy

Tumor-derived alpha-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells

Several tumor-derived factors have been implicated in DC dysfunction in cancer patients. Alpha-fetoprotein (AFP) is an oncofetal antigen that is highly expressed in abnormalities of prenatal development and several epithelial cancers, including hepatocellular carcinoma (HCC). In HCC patients exhibiting high levels of serum AFP, we have observed a lower ratio of myeloid-to-plasmacytoid circulating DC compared to patients with low serum AFP levels and healthy donors, suggesting that AFP alters DC differentiation in vivo. To test the effect of AFP on DC differentiation in vitro, peripheral blood monocytes from healthy donors were cultured in the presence of cord blood-derived normal AFP (nAFP) or HCC tumor-derived AFP (tAFP), and DC phenotype and function was assessed. Although the nAFP and tAFP isoforms only differ at one carbohydrate group, low (physiological) levels of tAFP, but not nAFP, significantly inhibited DC differentiation. tAFP-conditioned DC expressed diminished levels of DC maturation markers, retained a monocyte-like morphology, exhibited limited production of inflammatory mediators, and failed to induce robust T cell proliferative responses. Mechanistic studies revealed that the suppressive activity of tAFP is dependent on the presence of low molecular weight (LMW) species that i) co-purify with tAFP, and ii) are abundant in the LMW fractions of both tumor and non-tumor cell lysates. These data reveal the unique ability of tAFP to serve as a chaperone protein for ubiquitous LMW molecules, which function cooperatively to impair DC differentiation and function. Therefore, novel therapeutic approaches that antagonize the regulatory properties of tAFP will be critical to enhance immunity and improve clinical outcomes

Tumor-derived alpha fetoprotein directly impacts human natural killer cell activity and viability

Alpha-fetoprotein (AFP) is an oncofetal antigen produced by hepatocellular carcinomas (HCC). Previous studies demonstrated that tumor-derived AFP (tAFP) is a glycoprotein that has an immunosuppressive role on natural killer (NK), T, B, and dendritic (DC) cells which may play a role in HCC pathogenesis. Defects in NK cells have been attributed to tAFP-mediated immunosuppression of DC. However, a direct tAFP effect on NK cells remains unexplored. Here we compared the ability of cord blood-derived AFP (nAFP) to that of tAFP to modulate human NK cell activity and longevity in vitro. Short-term exposure to tAFP and, especially, nAFP proteins induced a unique pro-inflammatory, IL-2 hyperresponsive phenotype in healthy donor NK cells as measured by CD69 upregulation, IL-1β, IL-6 and TNF secretion, and enhanced tumor cell killing. In contrast, extended co-culture with tAFP, but not nAFP, inhibited NK cell proliferation and viability. NK cell activation was directly mediated by the AFP protein itself, while their viability was affected by the low molecular mass cargo that co-purified with tAFP. Overall, these data show that nAFP and tAFP induce similar yet distinct changes in NK cell function and viability, respectively. Defining the impact of circulating AFP on NK cells may be crucial to understand the NK cell functional deficits described in HCC patients

Unique challenges and clinical opportunities

hepatocellular carcinom

A Phase III open-label trial to evaluate efficacy and safety of CPI-613 plus modified FOLFIRINOX (mFFX) versus FOLFIRINOX (FFX) in patients with metastatic adenocarcinoma of the pancreas

Devimistat (CPI-613®) is a novel lipoate analog that inhibits the tricarboxcylic acid cycle at two key carbon entry points. Through its inhibition of pyruvate dehydrogenase and a-ketoglutarate dehydrogenase complexes, devimistat inhibits the entry of glucose and glutamine derived carbons, respectively. Pancreatic cancer is dependent on mitochondrial function for enhanced survival and aggressiveness. In a Phase I study of modified FOLFIRINOX, in combination with devimistat for metastatic pancreatic cancer patients, there was a 61% objective response rate including a 17% complete response rate. This report outlines the rationale and design of the AVENGER 500 study, a Phase III clinical trial of devimistat in combination with modified FOLFIRINOX compared with FOLFIRINOX alone for patients with previously untreated metastatic adenocarcinoma of the pancreas. Clinical trial registration: NCT03504423.status: publishe