Eugene Kennedy

CD4+ T cells pass through an effector phase during the process of in vivo tolerance induction.

An important process in the generation of tolerance to peripheral self-Ags is the induction of unresponsiveness in mature specific T cells. Although the end stage of this process, termed anergy, is well defined, the pathway by which naive T cells become anergic remains to be elucidated. Using an in vivo self-tolerance model, we demonstrate that CD4+ T cells pass through a significant effector stage on their way to an anergic state. This stage is characterized by production of effector cytokines, provision of help for CD8+ T cells, and induction of in vivo pathology within organs that express cognate Ag. These results suggest that the initial activation stage in T cell tolerance is similar to that seen in memory induction. They also suggest that autoimmune pathology can result during the natural process of tolerance induction rather than requiring that tolerance be broken.

Genetics of colorectal cancer.

Recent years have brought great advances in the understanding of the pathogenesis of colorectal cancers. The elucidation of the underlying genetic alterations that produce these cancers has made it possible to broadly categorize this disease into two major types, hereditary and sporadic. The hereditary cancers have been divided further into recognized syndromes, mainly familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. These syndromes have unique clinical pictures and different prognoses in addition to their different genetic bases. Sporadic cancers have been found to have analogous genetic alterations which propel them along the progression from normal tissue to benign adenoma/dysplasia to malignancy. These advances in genetics can potentially lead to clinically useful advances in detection, treatment, and, ultimately, prevention of colorectal cancer.

Abstract CT117: Interim analysis of the Phase 2 clinical trial of the IDO pathway inhibitor indoximod in combination with pembrolizumab for patients with advanced melanoma

Background: The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that normally inhibits immune responses when appropriate. In the setting of cancer, IDO pathway-mediated immune suppression is exploited by tumors in order to prevent and defeat anti-tumor immunity. Small-molecule inhibitors of the IDO pathway, such as indoximod, are an increasingly validated class of potential cancer therapeutics. Additionally, pre-clinical tumor models have shown complementary effects with indoximod / anti-PD1 checkpoint inhibitor treatment combinations. A clinical trial was developed based upon these data. Methods: Upon successful completion of a Phase 1b dose escalation cohort, metastatic melanoma patients were enrolled in a single arm Phase 2 trial evaluating the addition of indoximod to standard of care checkpoint inhibitors approved for melanoma. Treating physicians were allowed to administer their choice of approved checkpoint inhibitor. The large majority of patients received indoximod with pembrolizumab and this interim report is limited to those patients. Indoximod was administered continuously in 21 days cycles (1200mg po twice daily) concurrently with pembrolizumab (3mg/kg q21 days). Study endpoint is best overall response (objective response rate (ORR) = complete response rate (CR) + partial response rate (PR)) per site reported RECIST criteria. Results: At time of data cut-off, 60 patients had received indoximod /pembrolizumab and were evaluable for response, defined as having at least one follow-up imaging study performed. The ORR was 52% (31/60) with a CRR of 8% (5/60). The combination was well tolerated. The most frequently reported adverse events (regardless of attribution), occurring in ≥ 20% of subjects, were fatigue, diarrhea, nausea, arthralgia, headache, cough, rash, pruritus, and hypertension. The most frequently reported laboratory abnormalities (regardless of attribution), were anemia (17%) and hyperglycemia (17%). Conclusions: The interim analysis of the combination of indoximod and pembrolizumab demonstrates an ORR of 52% which compares favorably with the established ORR for pembrolizumab alone. Updated data to be presented. NCT02073123. Citation Format: Yousef Zakharia, Robert McWilliams, Monaster Shaheen, Kenneth Grossman, Joseph Drabick, Mohammed Milhem, Olivier Rixie, Samir Khleif, Ryan Lott, Eugene Kennedy, David Munn, Nicholas Vahanian, Charles Link. Interim analysis of the Phase 2 clinical trial of the IDO pathway inhibitor indoximod in combination with pembrolizumab for patients with advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT117. doi:10.1158/1538-7445.AM2017-CT117

A Phase I study of NLG919 for adult patients with recurrent advanced solid tumors

Meeting abstracts Clinical Trial Registration Number: [NCT02048709][1] The enzyme Indoleamine 2,3-dioxygenase (IDO1) catalyzes the cleavage of L-tryptophan, resulting in the production of kynurenine. Tryptophan depletion and kynurenine metabolites enhance the number and function of Tregs (

Real-world evidence (RWE) to show improved time to progression among resected pancreatic cancer (RPC) patients receiving adjuvant chemotherapy (adjch).

242Background: Two recent clinical trials (IMPRESS and APACT) suggest the overall survival (OS) of patients with resected pancreatic cancer (RPC) is far longer than previously believed. Improvements in patient selection, intra/post-operative surgical care adjch are suggested as explanations for the improved OS. RWE of time to progression (TTP) from surgery were calculated to assess if the results of these trials are generalizable. Methods: RPC patients (ICD-9=157.x, excluding 157.4; CPT=48140, 48146, 48150, 48152-5) diagnosed between 03/2012-06/2015 were selected from the Inovalon More2 administrative claims database. Adjch was defined as initiating chemotherapy within 90 days of surgery. TTP was the time from surgery until the first claim for metastatic disease (ICD-9 =196.0-.3, .5-.6, 197.0-.8, 198.0-.8) using the Kaplan-Meier method. Patients without a metastatic diagnosis during their follow-up were censored at 12 months to adjust for underreporting of metastatic disease codes in claims. Results: 1,01...

Abstract CT087: Phase II trial of theiIndoleamine 2, 3-dioxygenase pathway (IDO) inhibitor indoximod plus immune checkpoint inhibitors for the treatment of unresectable stage 3 or 4 melanoma

Background: IDO is an enzyme that catalyzes the initial and rate limiting step in the conversion of tryptophan to kynurenine. Tryptophan depletion enhances the number and function of the Treg (suppressive) arm of the immune system and inhibits the effector T cell (stimulatory) arm. In addition, it has been shown that kynurenine metabolites may augment the suppressive effects on inflammation and immune responses. The normal physiologic function of IDO is the regulation of acquired local and peripheral immune tolerance. In cancer, IDO can either be expressed directly by the tumor cells themselves, or induced indirectly in host antigen presenting cells by the presence of tumor. In these settings, the IDO pathway mediates an acquired immune tolerance towards tumors, allowing tumors to thwart an immune response by the host. Therefore, the IDO pathway is an attractive target. Anti- CTLA-4 (ipilimumab) and anti-PD-1 (pembrolizumab and nivolumab) are monoclonal antibodies that block the immunosuppressive receptor CTLA-4/ PD-1 on T cells, thus enhancing immune responses against tumors. Tumor models have shown synergistic effects with anti-CTLA-4 treatment and anti-PD-1 treatment in combination with indoximod providing a rationale for combination therapy for the treatment of melanoma. The phase 1b study has enrolled 9 patients combining a dose escalation indoximod (twice daily oral dose, continuously for each 21 day cycle) with ipilimumab (3mg/kg q3 weeks x 4 doses) in a standard 3+3 design. The phase II dose for indoximod has been established at 1200 mg twice daily (BID), which is the maximum biologically achievable dose of oral indoximod. Methods: This is an ongoing multicenter phase II clinical trial combining indoximod 1200 mg BID with provider choice of a standard of care immune checkpoint inhibitor, consisting of 4 cycles of concomitant ipilimumab, repeat cycles of nivolumab or repeat cycles of pembrolizumab. In the event of progression, the provider can change therapy from one checkpoint inhibitor (anti-CTLA-4 or anti-PD-1) to another (ipilimumab to pembrolizumab or nivolumab as well as pembrolizumab or nivolumab to ipilimumab) while continuing indoximod. In the case of toxicity requiring stoppage of checkpoint blockade with either anti-CTLA-4 or anti-PD-1 treatment patients can continue on indoximod monotherapy until progression. Eligible patients have unresectable Stage 3 or 4 melanoma. Up to 96 subjects are planned to enroll in phase II. Treatment can be continued until disease progression on sequential checkpoint blockade or toxicity. Primary objective is overall response rate, secondary objectives median progression free and overall survival. Correlative studies include qualitative analysis of IDO expression by immunohistochemistry in tumor samples. ClinicalTrials.gov Identifier: NCT02073123 Citation Format: Yousef Zakharia, Joseph Drabick, Samir Khleif, David Munn, Charles Link, Nicholas Vahanian, Eugene Kennedy, Montaser Shaheen, Olivier Rixe, Mohammed Milhem. Phase II trial of theiIndoleamine 2, 3-dioxygenase pathway (IDO) inhibitor indoximod plus immune checkpoint inhibitors for the treatment of unresectable stage 3 or 4 melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT087.