Biologics have emerged as a powerful and diverse class of molecular and cell-based therapies that are capable of replacing enzymes, editing genomes, targeting tumors, and more. As this complex array of tools arises a distinct set of challenges is rarely encountered in the development of small molecule therapies. Biotherapeutics tend to be big, bulky, polar molecules comprised of protein and/or nucleic acids. Compared to their small molecule counterparts, they are fragile, labile, and heterogeneous. Their biodistribution is often limited by hydrophobic barriers which often restrict their administration to either intravenous or subcutaneous entry routes. Additionally, their potential for immunogenicity has proven to be a challenge to developing safe and reliably efficacious drugs. Our discussion will emphasize immunogenicity in the context of therapeutic proteins, a well-known class of biologics. We set out to describe what is known and unknown about the mechanisms underlying the interplay between antigenicity and immune response and their effect on the safety, efficacy, pharmacokinetics, and pharmacodynamics of these therapeutic agents.

338 Background: Human Myeloid Derived Suppressor Cells (MDSCs) have gained recognition as a significant population of cells that arise in cancer patients to mediate immune tolerance. MDSCs have been validated as a prognostic factor in several tumor types. The Neutrophil-Lymphocyte Ratio (NLR) is an easily obtained marker of inflammation that has also been validated as a prognostic marker in tumors including prostate cancer. We measured and compared MDSC concentrations and NLR in a cohort of patients with prostate cancer and also examined thier relationship with PSA Progression, a validated marker of overall survival. Methods: Blood was collected from patients with localized prostate cancer (n = 14) and mCRPC (n = 44) at 0 and 6 months. The percent CD33+ HLA-DRlow HIF1a+, CD33+ HLADRlow C/EBPb+, CD11b+ HLA-DRlow HIF1a+, and CD11b+ HLA-DRlow C/EBPb+cells as a fraction of PBMC were determined and reported. NLRs were obtained within 4 weeks of MDSC measurements. Patients were followed for a period of 2 years; PSA-Progression (PSA-P) was defined as a PSA doubling time of < 3 months in association with an increase of at least > 5ng/mL from PSA nadir Results: Higher Gleason scores were statistically associated with a NLR of greater than 2 (r = 0.07, p = 0.02, 95% CI [0.01-0.14]). Increasing MDSC% did not correlate with increasing Gleason scores (r = 0.13, p = 0.31) or predict PSA-P at 6 months (p = 0.16). MDSC% in patients with mCRPC (4.25%, 95% CI[3.34-5.17]) were significantly higher than localized prostate cancer (1.7%, 95% CI[1.02-2.37]) . There was a highly statistically significant relationship between the percentage of MDSC in PBMC with the neutrophil lymphocyte ratio (r = 0.68, p = 0.001, 95% CI [0.31-1.05]). Conclusions: MDSC concentrations in metastatic prostate cancer patients are significantly higher than those with localized disease and are associated with an increased neutrophil lymphocyte ratio. Although a trend was detected towards MDSC% predicting PSA-P, in this limited sample it was not statistically significant.

TPS713 Background: Human Myeloid Derived Suppressor Cells (MDSCs) have gained recognition as a significant population of cells that arise in cancer patients to mediate immune tolerance. Some studies have shown MDSC concentrations to be associated with overall survival and response to therapy in renal cell carcinoma. MDSCs comprise a heterogenous population that are yet to be fully characterized. We have identified a set of biomarkers uniquely expressed by the suppressive human MDSC phenotype and have developed an assay targeted to these markers. MDSCs are potentially a relatively cheap and easily performed screening and monitoring tool in cancers. This study will examine how a proprietary clinical assay works in detecting and monitoring MDSCs in blood and urine samples from patients with localized or metastatic renal cell cancer. Methods: The pilot research trial will enroll 63 subjects in a 1:1:1 ratio in three groups, normal controls over age 40 without evidence of any malignancy, patients with metastatic disease and localized renal cell carcinoma prior to nephrectomy. This sample size provides 80% power to detect a 1SD difference in MDSC concentrations in these groups on an F test. Blood and urine samples will be drawn at baseline and at 4 months for comparison. The percent CD33+ HLA-DRlow HIF1a+, CD33+ HLADRlow C/EBPb+, CD11b+ HLA-DRlow HIF1a+, and CD11b+ HLA-DRlow C/EBPb+cells as a fraction of PBMC will be determined. Primary Outcome Measures will be 1. Change in MDSC levels in patients with known localized renal cell carcinoma who undergo surgical treatment. 2. Change in MDSC level in patients with known metastatic renal cell carcinoma who initiate systemic treatment and 3. The direction and magnitude of the changes compared with radiographically assessed tumor burden. Secondary outcome measures are to assess MDSC level measurements in urine cytology analysis at baseline and after treatment to determine whether the two tests correlate in any of the 3 groups of patients defined in this study. Conclusion: This pilot study will examine if a MDSC clinical assay works in detecting and monitoring MDSCs. Recruitment is open to patients at the USC Cancer center and LAC+USC medical center. Clinical trial information: NCT02664883.

TPS110 Background: Human Myeloid Derived Suppressor Cells (MDSCs) have gained recognition as a significant population of cells that arise in cancer patients to mediate immune tolerance. Some studies have shown MDSC concentrations to be associated with overall survival and response to therapy in urothelial carcinoma. MDSCs comprise a heterogenous population that are yet to be fully characterized. We have identified a set of biomarkers uniquely expressed by the suppressive human MDSC phenotype and have developed an assay targeted to these markers. MDSCs are potentially a relatively cheap and easily performed screening and monitoring tool in cancers. This study will examine how a proprietary clinical assay works in detecting and monitoring MDSCs in blood and urine samples from patients with or without localized or metastatic bladder cancer. Methods: The pilot research trial will enroll 63 subjects in a 1:1:1 ratio in three groups, normal controls over age 40 without evidence of any malignancy, patients with metastatic disease and localized muscle invasive disease prior to cystectomy. This sample size provides 80% power to detect a 1SD difference in MDSC concentrations in these groups on an F test. Blood and urine samples will be drawn at baseline and at 4 months for comparison. The percent CD33+ HLA-DRlow HIF1a+, CD33+ HLADRlow C/EBPb+, CD11b+ HLA-DRlow HIF1a+, and CD11b+ HLA-DRlow C/EBPb+cells as a fraction of PBMC will be determined. Primary Outcome Measures will be 1. Change in MDSC levels in patients with known localized, muscle-invasive bladder cancer who undergo neoadjuvant and surgical treatment. 2. Change in MDSC level in patients with known metastatic bladder cancer who undergo systemic treatment and 3. The direction and magnitude of the changes compared with radiographically assessed tumor burden. Secondary outcome measures are to assess MDSC level measurements in urine cytology analysis at baseline and after treatment to determine whether the two tests correlate in any of the 3 groups of patients defined in this study. Conclusion: This pilot study will examine if a MDSC clinical assay works in detecting and monitoring MDSCs. Recruitment is open to patients at the USC Cancer center and LAC+USC medical center. Clinical trial information: NCT02735512.