Human Immune Responses to Tumor Antigens for Cancer Immunotherapy

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study: Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT034876660) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. In the study, a combination of nivolumab plus capecitabine led to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) is associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence. Serum analytes as predictors of disease recurrence and the duration of invasive disease-free survival in patients with triple negative breast cancer enrolled in the OXEL trial treated with immunotherapy, chemotherapy, or chemoimmunotherapy: We previously reported on the primary endpoint of the OXEL trial, demonstrating that a peripheral immunoscore based on circulating immune cells reflecting immune activation was increased in patients treated with immunotherapy. However, compared with cell-based immune assays, sera assays are more cost-effective, less labor-intensive, and samples easier to obtain. In the current study, we report on differences in serum analytes between treatment arms and associations with clinical response. Patients (n=38) were assayed for 97 serum analytes before and after 6 and 12 weeks of therapy. Serum analytes were assessed for changes with therapy, and as predictors of disease recurrence and the duration of invasive disease-free survival (iDFS) in both single analyte analyses and machine learning models. Levels of specific analytes at baseline and changes in levels at early time points on treatment preceding recurrence were associated with eventual development of disease recurrence and/or the duration of iDFS. These associations varied based on the therapy patients received. Immunotherapy led to enrichment in pro-inflammatory analytes following treatment, whereas chemotherapy resulted in overall decreases. Changes seen in patients receiving chemoimmunotherapy more closely resembled those observed in patients receiving immunotherapy alone as opposed to chemotherapy alone. Furthermore, logistic regression and Cox proportional hazard models, developed using machine learning methods, demonstrated that combinations of serum analytes were more predictive of disease recurrence and iDFS duration than analyses of single serum analytes. Notably, the multivariable models that predicted patient outcomes were highly specific to the class of treatment patients received. In patients with TNBC with residual disease after neoadjuvant chemotherapy, treatment with immunotherapy alone or chemoimmunotherapy resulted in enhanced immune activation compared with chemotherapy alone as measured by changes in serum analyte levels. Distinct serum analytes, both at baseline and as changes after therapy, predicted clinical outcomes for patients receiving immunotherapy alone, chemotherapy alone, or chemoimmunotherapy. PRGN-2009 and bintrafusp alfa for patients with advanced or metastatic human papillomavirus-associated cancer: This first-in-human phase 1 study (NCT04432597) evaluated the safety and recommended phase 2 dose (RP2D) of PRGN-2009, a gorilla adenoviral-vector targeting oncoproteins E6, E7 (human papillomavirus (HPV)16/18) and E5 (HPV16), as monotherapy (Arm 1A) and combined with the bifunctional TGF-beta "trap"/anti-PD-L1 fusion protein bintrafusp alfa (BA; Arm 1B), in patients with recurrent/metastatic HPV-associated cancer. Patients with greater than or equal to 1 prior treatment (immunotherapy allowed) received PRGN-2009 (1 × 1011 particle units or 5 × 1011 particle units, subcutaneously) every 2 weeks for 3 doses, then every 4 weeks (Arm 1A), or PRGN-2009 (RP2D, schedule per Arm 1A) and BA (1200 mg, intravenously) every 2 weeks (Arm 1B). Primary endpoints were safety and RP2D of PRGN-2009; secondary objectives included overall response rate (ORR) and overall survival (OS). Seventeen patients were treated. In Arm 1A (n = 6) there were no dose limiting toxicities or grade 3/4 treatment-related adverse events (TRAEs), 5 × 1011 PU was selected as RP2D, no responses were observed, and median OS (mOS) was 7.4 months (95% CI 2.9-26.8). In Arm 1B (n = 11), grade 3/4 TRAEs occurred in 27% of patients, ORR was 20% for all patients (22% in checkpoint-resistant patients), and mOS was 24.6 months (95% CI 9.6-not reached). Multi-functional HPV-specific T cells were increased or induced de novo in 80% of patients and not impacted by anti-vector antibodies. Higher serum IL-8 at baseline associated with shorter OS. PRGN-2009 was well tolerated, and immune responses were observed to PRGN-2009. Encouraging anti-tumor activity and OS were noted in the combination with BA arm, consisting mainly of checkpoint-resistant patients. PRGN-2012 gene therapy in adults with recurrent respiratory papillomatosis: a pivotal phase 1/2 clinical trial: Recurrent respiratory papillomatosis (RRP) is a rare debilitating condition caused by chronic infection with human papillomavirus (HPV) type 6 or 11. Papillomas develop in the aerodigestive tract, leading to significant voice disturbance and airway obstruction. No systemic treatment currently exists. We aimed to assess the safety and clinical activity of PRGN-2012 in adult patients with RRP treated at the recommended phase 2 dose. This was a single-center, single-arm, phase 1/2 trial (NCT04724980). Adult patients aged 18 years or older with RRP who required three or more interventions in the 1 year before treatment received adjuvant PRGN-2012 on day 1 following surgical debulking of disease, and on days 15, 43, and 85. Primary outcome measure was complete response rate, defined as the percentage of patients who did not require an intervention to control RRP in the 12 months after treatment. Safety outcomes included treatment-related adverse events. From March 16, 2021, to June 1, 2023, 38 patients were enrolled and received the 12-week treatment course. Among the 35 patients treated at the recommended phase 2 dose of 5×1011 particle units, 18 (51%) of 35 patients had a complete response (95% CI 34-69) with the median duration of complete response yet to be reached. Adverse events were mild and included grades 1-2 injection site reaction (34 [97%] of 35), fatigue (28 [80%] of 35), chills (25 [71%] of 35), and fever (24 [69%] of 35). PRGN-2012 treatment resulted in complete response in 51% of the patients treated and was safe. Based on these positive pivotal study results, a biologics license application to the US Food and Drug Administration (FDA) is planned, positioning PRGN-2012 to be an FDA-approved medical treatment for adult patients with RRP.