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Background: Indoleamine 2,3 dioxygenase (IDO) is a tryptophan-catabolizing enzyme that causes immunosuppression in the tumor microenvironment. Indoximod is an IDO pathway inhibitor. Preclinical data suggests indoximod enhancs the activity of dendritic cell (DC) vaccines. Ad.p53 is an adenovirus used to generate autologous dendritic cell (DC) vaccines against p53 epitopes. We initiated a phase 1/2a trial of indoximod + Ad.p53DC to explore the safety and efficacy of the combination along with response to subsequent chemo. The phase 1 safety data were previously presented and the treatment was well tolerated with no DLTs. (Soliman, ASCO 2013) This abstract includes new phase 2a safety/efficacy data and updated outcomes on all phase 1/2 metastatic breast cancer patients who received Adp53DC+indoximod and any subsequent response to salvage chemo. Methods: The phase 2a study combined indoximod 1600mg PO BID with up to 6 Ad.p53 DC vaccinations q2wks. The trial used a single arm, Simon two stage design (n=12 in 1st stage, 25 in 2nd stage) with objective response as the primary endpoint. One response out of 12 was required for progression into second stage. The study had 90% power to detect 20% response rate with a p=.09. Patients with measurable, metastatic breast cancer, 5%, ECOG 0-2, no autoimmune disease were eligible. Study treatment continued until disease progression or unacceptably toxicity. Results: Twelve phase 2 patients were accrued, 9 (7 TNBC, 2 ER+/HER2-) received ≥ 1 dose of Ad.p53DC+indoximod (3 did not due to rapid disease progression during vaccine preparation). Six patients had ≥ 1 prior line of chemo. Seven (58%) subjects experienced any grade AE, there were no treatment related AEs ≥G3. All treatment attributable AEs were G1-2, Conclusions: Indoximod+Ad.p53DC was well tolerated. Across phase 1/2 the best response to immunotherapy alone was SD in 4 pts while 10 of 21 (47%) (including 1 CR) responded to subsequent chemotherapy in this largely pretreated cohort. There may be a chemosensitization effect of indoximod+Ad.p53DC. Future trials should combine this treatment with chemotherapy in appropriately selected patients. Citation Format: Hatem H Soliman, Susan E Minton, Roohi Ismail-Khan, Hyo S Han, Nicholas N Vahanian, Charles J Link, Gene Kennedy, Howard Streicher, Daniel Sullivan, Scott J Antonia. A phase 1/2 study of Ad.p53 DC vaccine with indoximod immunotherapy in metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-15-04.

The immunosuppressive enzyme, indoleamine 2,3 dioxygenase (IDO), is overexpressed in many different tumor types including breast cancer. IDO inhibitors synergize with chemotherapy in breast cancer murine models. Characterizing IDO expression in breast cancer could define which patients receive IDO inhibitors. This study analyzed IDO protein expression in 203 breast cancer cases. The relationship between IDO, overall survival (OS), disease-specific survival (DSS), clinicopathologic, molecular, and immune tumor infiltrate factors was evaluated.Expression of IDO, estrogen receptor (ER), progesterone receptor (PR), human epithelial receptor 2, cytokeratin 5/6, epithelial growth factor receptor, phosphorylated AKT, neoangiogenesis, nitrogen oxide synthetase 2 (NOS2), cyclooxygenase 2 (COX2), FoxP3, CD8, and CD11b on archival breast cancer tissue sections was evaluated by immunohistochemistry. Associations between IDO and these markers were explored by a univariate and multivariate analysis. Survival was analyzed using Kaplan-Meier (OS) and Wilcoxon two-sample (DSS) tests.IDO expression was higher in ER+ tumors compared to ER- tumors. IDO was lower in those with higher neoangiogenesis. OS was better in ER+ patients with high IDO expression. DSS was better in node-positive patients with high IDO expression. IDO activity positively correlates with NOS2. COX2 as positively correlated with IDO on univariate but not multivariate analysis. There was a trend toward greater numbers of CD11b+ cells in IDO-low tumors.IDO protein expression is lower in ER- breast tumors with greater neoangiogenesis. Future clinical trials evaluating the synergy between IDO inhibitors and chemotherapy should take this finding into account and stratify for ER status in the trial design.

The results of recent clinical trials have demonstrated that cancer vaccines continue to struggle to achieve tangible clinical benefits as monotherapy. Tumor-induced abnormalities in the immune system hamper anti-tumor T cell responses limiting the effectiveness of cancer immunotherapy. Recently, evidence has been mounting to suggest that immunotherapy has the possibility of achieving better success when used in combination with conventional chemotherapy. In clinical trials, immune responses elicited by cancer vaccines appear to augment the effectiveness of subsequent conventional cancer therapies.

Background Indoleamine 2,3dioxygenase (IDO) is a tryptophan-catabolizing enzyme that plays a key role in the regulation of immune tolerance. Tumors also employ this mechanism to induce a state of immunosuppression, evading immune mediated destruction. Indoximod (D-1-methyltryptophan) is a broad IDO pathway inhibitor as it has been shown to potentially interfere with multiple targets within the IDO pathway. Preclinical studies in MMTV-neu mouse models have shown that indoximod combined with chemotherapy was more effective in causing tumor regressions than either agent alone. A phase 1 trial combining docetaxel and indoximod demonstrated safety and responses in metastatic breast cancer patients. Based on this data a phase 2 trial in first line metastatic breast cancer was initiated. Trial design The study is a 1:1 randomized, placebo controlled two arm phase 2 study. The study treatment is docetaxel 75mg/m2 IV D8 plus indoximod 1200mg PO BID D1-14 every 21 days or matching placebo. Primary endpoint is progression free survival. Secondary endpoints include overall survival, response rate, and immune response correlative assays. Patients with measurable, histologically confirmed metastatic breast cancer, no prior chemotherapies (hormonal therapies allowed) in the metastatic setting, ER+ or ER –, HER2 -, ECOG PS 0-1, no active CNS disease, no active autoimmune disease are eligible. Target enrollment is 154 patients. The trial is currently open at multiple clinical sites all around the US and actively enrolling patients. Expansion to the EU is underway. NCT01191216. Disclosure E.P. Kennedy: Employee of NewLink Genetics who is the sponsor for this clinical trial; G. Rossi: Author is an employee of NewLink Genetics; N. Vahanian and C. Link: Author is an officer and employee of NewLink Genetics. All other authors have declared no conflicts of interest.

3012 Background: Although ES-SCLC is initially, very responsive to CT, responses are not durable and relapse is characterized by chemoresistance. High incidence of p53 gene mutations, which prolong the protein’s half life, result in its frequent overexpression and enhanced detection in SCLC cells. This in turn allows for their recognition by p53-specific cytotoxic T cells. Here, we evaluated the clinical and immune response of a vaccine (vac) using p53-DC. Methods: Eligibility: Untreated, ES-SCLC pts. Age = 18 years. Performance status (PS) 0–2. Treated and controlled brain metastases. Adequate renal, hepatic and bone marrow function. Toxicity (T), survival (MST) and clinical and p53- specific immune responses were determined by CTCAE v2.0, Kaplan-Meier, RECIST and ELISPOT and tetramer staining respectively. Pts first received CT to best clinical response. Eight weeks later, those with minor progression (PD) or better, underwent leukapheresis. DC, generated from peripheral blood precursors, were infected with an adenoviral construct containing p53 (Advexin; Ad-p53) to produce the p53-DC vac. Each vaccination consisted of subcutaneous injections in 4 different nodal basins every 2 weeks x3 (2–5×106 p53-DC/dose). Results: Thirty-six pts received at least one vac; median age=58.8, (range=39–79), M/F=13/23, PS 0/1=16/20. All pts were evaluable for T and MST. Total vac=127 (median=3, range=2–6). Overall, vac was well tolerated (no > grade 2 toxicities detected). p53-specific immune response was positive in 11/21 (52.4%) pts; pending in 15 pts. After 3 vac doses, 10 (27.7%) pts. had stable disease (SD) and 26 (72.2%) had PD. Pts with SD were re-vaccinated (x3). Upon PD, all pts were offered further CT. Clinical response to post-vac CT was evaluated in 22 pts. Ten pts (45%) responded to post-vac CT (second line=7, third line=3) and 6 pts had SD. MST=473 days (95% CI: 380,534). Conclusions: ES-SCLC pts were treated safely with p53-DC vaccine and demonstrated significant immune response. The p53-DC vaccine appears to sensitize ES-SCLC to subsequent CT resulting in improved survival. [Table: see text]

7690 Background: Adding G to first-line doublet chemotherapy did not improve survival in comparison to doublet chemotherapy alone in phase III trials (INTACT 1 and INTACT2). We hypothesized that therapy with D and G will yield similar efficacy to doublet chemotherapy but with improved toxicity profile that would be especially meaningful for elderly patients. We report here the results of a completed phase II trial. Methods: Previously untreated elderly patients with ANSCLC with ECOG performance status (PS) of 0 or 1, were eligible. D was given at 75 mg/m2 IV on day1, Q 21 days. G given orally daily; starting day 1, at a dose of 250mg. D-G was given for 2 cycles beyond maximal response. G was continued until progression. Tumors were assessed every two cycles while on D-G and every two months while on G. The RECIST criteria were used to measure responses. Results: Forty-four eligible patients were enrolled from 07/2003 to 11/2005. Demographic characteristics were M/F = 25/19; Median age 75 years (range; 70 to 84 years); ECOG PS 0/1= 27/16; Stage IV/IIIB = 38/6; Never-smoker/smoker 8/36; Adenocarcinoma/non-adeno-NSCLC 30/14; Median number of D-G cycles administered is 4 (range; 1 to 6). Median duration on maintenance D was 5 months (range; 1 to 36) Overall response rate was 29% (CR- 2%; PR- 27%) with 48% stable disease. Median progression free survival (PFS) was 8 months (95% CI: 6.2–10.6), PFS at 12 months was 34%, and 24 months was 19%. Median Overall Survival (OS) was 12 months (95% CI: 5.6–17.5). OS at 12 months was 52% and 24 months was 20%. The most common hematologic and non- hematologic adverse events were lymphopenia/anemia, and fatigue/hyperglycemia (steroid-induced)/dyspnea, respectively. Three patients had febrile neutropenia (6.8%). Detailed toxicity analyses will be reported at the meeting. Conclusion: The combination of D and G demonstrates comparable efficacy to conventionally used doublet chemotherapy regimens. The relatively favorable toxicity profile warrants further development of this approach, especially in clinical situations or special populations where toxicities are an impediment to treatment. No significant financial relationships to disclose.

2543 Background: Many types of cancer are associated with mutations in the p53 gene. Patients with SCLC exhibit a very high frequency of p53 mutations, which result in overexpression of p53 protein in tumor cells. In preclinical studies we and others have demonstrated that tumor cells can be recognized by p53-specific cytotoxic T cells. Here, we tested this concept in clinical trial. Methods: Twenty-two patients with extensive stage SCLC were treated to date in an on-going phase II trial. Patients received first-line chemotherapy to best response, and those patients with stable disease or minor progression underwent leukapheresis 8 weeks after the last dose of chemotherapy. DC were generated from peripheral blood precursors and then infected with adenoviral construct containing wild-type p53 (ADVEXIN). Patients received 3 doses of vaccine i.d. (2–5x106 p53+ DCs per dose). p53 specific immune response was evaluated using ELISPOT and staining with tetramers. Results: The vaccine was well tolerated, and no a...

7155 Background: Doublet chemotherapy with 2 cytotoxic drugs is considered standard therapy for ANSCLC. We report here the preliminary data from an on going phase II trial combining docetaxel and g...

7342 Background: Currently chemotherapy with two cytotoxic drugs is considered standard treatment for ANSCLC. We hypothesized that doublet therapy with a cytotoxic drug (docetaxel) and an EGFRTKI (...

Meeting abstracts Platinum-based doublets are standard of care (SoC) first-line treatment for advanced NSCLC, but durable benefit is observed infrequently, with resistance to chemotherapy invariably developing. The blockade of immune checkpoints is a promising novel approach in cancer treatment.