Discussion
NSCLC, tumor, colorectal cancer, TNF-α, neutropenia, toxicity, cancer, inflammation, Head and Neck Squamous Cell Carcinoma, SD, uterine carcinoma, PD, NRAS, HNSCC, tumors
TUMOR, METASTASIS, COLORECTAL CANCER, NEUTROPENIA, ONCOGENESIS, CANCER, INFLAMMATION, EVENT, SOLID TUMORS, ADVERSE EFFECT, NON-SMALL CELL LUNG CANCER, UTERINE CARCINOMA, OVARIAN CARCINOMA, CERVICAL CANCER, NSCLC, TUMORS, COMPLICATIONS
One of the mechanisms involved in cancer development, progression and metastasis is the disruption of post-translational modifications of proteins and lipids, such as glycosylation. One glycosylation pattern altered in cancer cells is the O-glycosylation. During oncogenesis, truncated O-glycans can be expressed. This occurs when N-acetyl galactosamine (O-GalNAc) is added to the amino acids serine and threonine on cancer cells’ carrier proteins [In contrast to many antitumor antibodies, which were developed against a normal human protein, NEO-201 was raised against immunogenic tumor extracts as part of an allogenic colorectal cancer vaccine program [A recent study showed that NEO-201 recognizes specifically core 1 and/or extended core 1 O-glycans, and that NEO-201 binds and kills target cells expressing core 1 and/or extended core 1 O-glycans, through ADCC [This manuscript reports the results of the first-in-human, phase I dose escalation study of anti-core 1 O-glycans mAb NEO-201 in patients with solid tumors. Pre-clinical toxicity studies performed in cynomolgus monkeys showed exceptional safety/tolerability of NEO-201, with a transient decrease in neutrophils being the only adverse effect observed [Aside from the expected complications of neutropenia, NEO-201 was otherwise well tolerated. As expected from the binding profile of NEO-201 in animal studies and in vitro [Correlative studies revealed that NEO-201 infusion resulted in an upregulation of serum IL-10 and TNF-α levels, with more variable effects on other proinflammatory cytokines such as IL-8 and IFNγ. These cytokines are all classically considered proinflammatory and are elevated during acute inflammation. If inflammation becomes chronic, IL-10 and TNF-α could also have effects that block antitumor immunity by promoting the expansion of immunosuppressive cells such as Tregs and myeloid-derived suppressor cells (MDSCs) [In this study, we observed only a transient elevation of TNF-α and IL-10 levels following NEO-201 administration. Levels of these cytokines decreased toward baseline by 72 h from infusion in all patients, suggesting that this elevation is an acute inflammatory event and that NEO-201 does not determine a prolonged elevation of these cytokines. In our ongoing Phase II study, we are performing further mechanistic studies to evaluate the modulation of these cytokines not only in the peripheral blood but also in the TMEWe did not observe a significant difference in serum levels of soluble CEACAM-5 and CEACAM-6 between patients with SD and PD. On the contrary, patients with SD showed much lower baseline and post treatment serum levels of MICA compared to patients with PD, although this difference was not statistically significant. Patients with PD, who had high soluble MICA levels, also showed an impairment of NK activation markers. Conversely, patients with SD, who had low soluble MICA levels, did not show an impairment of NK activation markers, suggesting that soluble MICA could be a factor involved in the impairment of NK antitumor activity. Our observations correlate with several studies that proved that high soluble MICA levels correlate with poor prognosis in cancer patients [Additional correlative immunophenotyping assays unexpectedly revealed that NEO-201 binds to a specific subset of highly immunosuppressive Tregs expressing the cell surface marker CD15s (sialyl-Lewis-X). CD15s is specifically expressed by activated, terminally differentiated and most suppressive FOXP3This first in human study confirms what was observed in pre-clinical studies. NEO-201 has a potent ADCC-mediated killing activity against its target cells (i.e. neutrophils), and its potency is correlated to the activation status of NK cells, as shown in patients with SD. However, this study presents some weaknesses that are being addressed in both ongoing and future planned clinical studies with NEO-201. One of the weaknesses of this study is that we enrolled mostly patients with colorectal cancer who, although had high expression of NEO-201 target antigen, may have some intrinsic resistance to the anti-tumor activity of NEO-201. These were heavily pretreated patients in whom standard therapies had failed. These patients had microsatellite stable status, for whom immunotherapy is not indicated. Several factors involved in the TME of patients with colorectal cancer, such as accumulation of Tregs, MDSCs, and immunosuppressive cytokines, have been reported to determine resistance to immunotherapy [In our study, we reported SD in 4 patients with colorectal cancer, and we observed that SD could be linked to the low baseline level of soluble MICA and reduction of circulating Tregs after treatment with NEO-201. It is possible that NEO-201 may have an effect in depleting Tregs in the TME. Unfortunately, in this study, we did not have the possibility to evaluate the antitumor effect of NEO-201 in the TME. In addition, due to small sample size and heterogeneous tumor types in this study, the interpretation of our correlative studies is limited.Moreover, we noticed that all patients with SD harbored mutations in KRAS and/or NRAS genes. Based on this observation we will continue to explore the impact of specific genetic alterations in several types of tumors on the efficacy of NEO-201 and to determine if there is a role in combining NEO-201 and precision cancer drugs based on specific genetic alterations.To overcome these issues, in our ongoing phase II clinical trial, we are a) enlarging sample size; b) including different types of tumors that could be more sensitive to the immunotherapy than colorectal cancer (metastatic Non-Small Cell Lung Cancer (NSCLC), cervical cancer, Head and Neck Squamous Cell Carcinoma (HNSCC), uterine carcinoma who have progressed during or after front-line standard of care treatment including chemotherapy, checkpoint therapy and/or targeted therapy; c) evaluating the antitumoral activity of NEO-201 in the TME, including its ability to deplete Tregs, and if Tregs depletion in the TME is correlated to the clinical response to NEO-201 in combination with pembrolizumab; d) using NEO-201 at the RP2D with better timing of administration of filgrastim; e) evaluating the correlation with low baseline levels of soluble MICA with the clinical response to treatment with NEO-201 with a bigger sample size. If this correlation will be linked to a statistically significant difference between responders and non-responders, low soluble MICA level will be included as one of the eligibility criteria to select a more specific population that may benefit from treatment with NEO-201.Another shortcoming is that neutrophils killed by NEO-201 through ADCC can act as a “sink”, removing NEO-201 from the bloodstream and reducing the amount of antibody available to kill tumor cells. To overcome this issue and maximize the level of NEO-201 available to the tumor we are planning to launch new studies to use NEO-201 with chemotherapy or other anti-cancer drugs during neutrophil nadir. This concept is reinforced by results obtained in animal models harboring human pancreatic and ovarian carcinoma, in which we tested the antitumor activity of NEO-201. In these animals, lacking circulating human neutrophils, NEO-201 showed a potent antitumor activity, resulting in a reduction of tumor volume and/or prolonged survival compared to controls [