31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

A phase I/Ib multicenter study to evaluate the humanized anti-CD73 antibody, CPI-006, as a single agent, in combination with CPI-444, and in combination with pembrolizumab in adult patients with advanced cancers

TPS2646 Background: CD73 expression is elevated in tumors and contributes to increasing levels of immunosuppressive adenosine in the tumor microenvironment. CD73 knockout mice exhibit reduced tumor growth and resistance to experimental metastasis. Inhibition of CD73 activity with an anti-CD73 antibody blocks adenosine production, shown to inhibit tumor growth in syngeneic models. CPI-006 is a humanized IgG1 FcγR binding-deficient anti-CD73 antibody now being investigated in this Phase 1/1b multicenter, open label trial as single agent (SA) or combination with CPI-444, an oral, small molecule, selective A2aR antagonist or in combination with pembrolizumab, an anti-PD1 indicated for the treatment of patients across a number of malignancies (NCT03454451). Methods: Up to 462 subjects will be enrolled at approximately 35 sites in the US, Canada and Australia. Eligible patients must have: non-small cell lung, renal cell carcinoma, urothelial bladder, cervical, colorectal, ovarian, pancreatic, prostate, head and neck, triple-negative breast, endometrial, select sarcomas and non-Hodgkin lymphoma malignancies relapsed, refractory or intolerant to 1 to 5 standard therapies; aged ≥ 18 yo; adequate organ function and measurable disease. The objectives of the study are 1) evaluate the safety and tolerability of SA CPI-006, in combination with CPI-444 and in combination with pembrolizumab, 2) evaluate the pharmacokinetics of each regimen and 3) identify potential biomarker signals predictive of response. Study design in table. Study Design. Clinical trial information: NCT03454451. [Table: see text

Immunobiology, preliminary safety, and efficacy of CPI-006, an anti-CD73 antibody with immune modulating activity, in a phase 1 trial in advanced cancers

2505 Background: CPI-006 inhibits CD73, a nucelotidase that converts AMP to adenosine and functions as a lymphocyte adhesion molecule. CPI-006 is a humanized IgG1 FcγR binding-deficient antibody that binds to CD73+ T and B lymphocytes leading to activation of B cells and expression of CD69. This study investigates the immunobiology, safety, and efficacy of CPI-006 monotherapy and in combination with CPI-444, an adenosine A2A receptor (A2AR) antagonist (NCT03454451). Methods: Patients with relapsed solid tumors were treated in a 3 + 3 escalation study with 1, 3, 6 or 12 mg/kg CPI-006 (Q3w IV infusion) monotherapy or in combination with CPI-444 (100 mg, PO, BID). Flow cytometry was performed on blood samples for lymphocyte subset analysis and receptor occupancy. Results: 17 patients were enrolled; 11 monotherapy and 6 combination. CPI-006 was associated with Grade 1 infusion reactions occuring within 30 minutes of the first infusion and were eliminated by premedication with non-steroidals. No DLTs with monotherapy or combination therapy were seen. Receptor occupancy on peripheral lymphocytes was maintained for the full dosing interval at 12 mg/kg. Pharmacodynamic effects suggesting immune modulation were observed within 1 hr of infusion at all dose levels and included a decrease in peripheral blood CD73pos B cells (mean reduction 86%, p < 0.05), increased CD73neg CD4 T cells (mean increase 37%, p < 0.01), and decreased CD8 T cells (mean reduction 20%, p < 0.01) compared to baseline. Overall, CD4:CD8 ratios were increased. Tumor regression was observed in a prostate cancer patient after 5 cycles of monotherapy at 6 mg/kg; peripheral B cells partially returned by the second cycle and reached a new homeostatic level through subsequent cycles. No change in serum immunoglobulins were observed. Conclusions: CPI-006 induces a rapid lymphocyte redistribution, including a transient reduction of circulating CD73pos B cells suggesting redistribution to lymphoid tissues, and an increased CD4:CD8 ratio, consistent with increased TH effector/memory cells in the blood. The treatment has been well-tolerated, and there is early evidence of anti-tumor activity of CPI-006 monotherapy. Clinical trial information: NCT03454451

First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRAS(G12C) Solid Tumors (KRYSTAL-1)

PURPOSE: Adagrasib (MRTX849) is an oral, highly selective, small-molecule, covalent inhibitor of KRAS(G12C). We report results from a phase I/IB study of adagrasib in non-small-cell lung cancer, colorectal cancer, and other solid tumors harboring the KRAS(G12C) mutation. MATERIALS AND METHODS: Patients with advanced KRAS(G12C)-mutant solid tumors were treated with adagrasib 150 mg orally once daily, 300 mg once daily, 600 mg once daily, 1,200 mg once daily, or 600 mg orally twice a day using an accelerated titration design, which transitioned to a modified toxicity probability interval design when a predefined degree of toxicity was observed or target adagrasib exposure was achieved. Safety, pharmacokinetics, and clinical activity were evaluated. RESULTS: Twenty-five patients were enrolled and received at least one dose of adagrasib. The recommended phase II dose (RP2D) was 600 mg twice a day on the basis of safety, tolerability, and observed pharmacokinetics properties. No maximum tolerated dose was formally defined. After a median follow-up of 19.6 months, eight of 15 patients (53.3%; 95% CI, 26.6 to 78.7) with RECIST-evaluable KRAS(G12C)-mutant non-small-cell lung cancer treated at 600 mg twice a day achieved a confirmed partial response. The median duration of response was 16.4 months (95% CI, 3.1 to not estimable). The median progression-free survival was 11.1 months (95% CI, 2.6 to not estimable). One of two patients with KRAS(G12C)-mutant colorectal cancer treated at 600 mg twice a day achieved a partial response (duration of response, 4.2 months). At the RP2D, the most common treatment-related adverse events (any grade) were nausea (80.0%), diarrhea (70.0%), vomiting (50.0%), and fatigue (45.0%). The most common grade 3-4 treatment-related adverse event was fatigue (15.0%). CONCLUSION: Adagrasib 600 mg twice a day was well tolerated and exhibited antitumor activity in patients with advanced solid tumors harboring the KRAS(G12C) mutation

SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase 1b, Multicenter Study

PD-1 inhibitors are approved for treating advanced melanoma, but resistance has been observed. This phase Ib trial evaluated intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9), in combination with pembrolizumab in patients with unresectable or metastatic malignant melanoma. The most common adverse events related to SD-101 were injection-site reactions and transient, mild-to-moderate "flu-like" symptoms. Among the 9 patients naïve to anti-PD-1 therapy, the overall response rate (ORR) was 78%. The estimated 12-month progression-free survival rate was 88%, and the overall survival rate was 89%. Among 13 patients having prior anti-PD-1 therapy, the ORR was 15%. RNA profiling of tumor biopsies demonstrated increased CD8+ T cells, natural killer cells, cytotoxic cells, dendritic cells, and B cells. The combination of intratumoral SD-101 and pembrolizumab was well tolerated and induced broad immune activation in the tumor microenvironment with durable tumor responses in both peripheral and visceral lesions.Significance: These early data demonstrate that the combination of pembrolizumab with intratumoral SD-101 is well tolerated and can induce immune activation at the tumor site. Combining an intratumoral TLR9 innate immune stimulant with PD-1 blockade can potentially increase clinical efficacy with minimal additional toxicity relative to PD-1 blockade alone. Cancer Discov; 8(10); 1250-7. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1195