Autogene cevumeran with or without atezolizumab in advanced solid tumors: a phase 1 trial

Effective targeting of somatic cancer mutations to enhance the efficacy of cancer immunotherapy requires an individualized approach. Autogene cevumeran is a uridine messenger RNA lipoplex-based individualized neoantigen-specific immunotherapy designed from tumor-specific somatic mutation data obtained from tumor tissue of each individual patient to stimulate T cell responses against up to 20 neoantigens. This ongoing phase 1 study evaluated autogene cevumeran as monotherapy (n = 30) and in combination with atezolizumab (n = 183) in pretreated patients with advanced solid tumors. The primary objective was safety and tolerability; exploratory objectives included evaluation of pharmacokinetics, pharmacodynamics, preliminary antitumor activity and immunogenicity. Non-prespecified interim analysis showed that autogene cevumeran was well tolerated and elicited poly-epitopic neoantigen-specific responses, encompassing CD4 + and/or CD8 + T cells, in 71% of patients, most of them undetectable at baseline. Responses were detectable up to 23 months after treatment initiation. CD8 + T cells specific for several neoantigens constituted a median of 7.3% of circulating CD8 + T cells, reaching up to 23% in some patients. Autogene cevumeran-induced T cells were found within tumor lesions constituting up to 7.2% of tumor-infiltrating T cells. Clinical activity was observed, including one objective response in monotherapy dose escalation and in two patients with disease characteristics unfavorable for response to immunotherapy treated in combination with atezolizumab. These findings support the continued development of autogene cevumeran in earlier treatment lines. ClinicalTrials.gov registration: NCT03289962

Effect of treatment-related lymphopenia on survival in newly diagnosed patients with resected adenocarcinoma of the pancreas.

270 Background: Severe treatment-related lymphopenia is associated with shorter survival in patients with high grade gliomas. This study was performed to determine if patients with resected pancreatic adenocarcinoma treated with post-operative radiation and chemotherapy develop significant lymphopenia and if this affects overall survival. Methods: Patients selected for this retrospective analysis underwent pancreatic cancer resection between 1997 and 2008, and received post-operative radiation with gemcitabine or 5-FU based chemotherapy at Johns Hopkins Hospital. Serial lymphocyte counts were recorded and survival was analyzed as a function of lymphopenia and known prognostic factors. Results: Fifty-three adults met the eligibility criteria. Their median age was 64, median tumor size was 3 centimeters, 83% underwent a pancreaticoduodenectomy, 47% had positive margins, and 92% had positive nodes. Total lymphocyte counts were normal in 91% of patients prior to receiving radiation and concomitant chemotherapy with 5FU(59%) or gemcitabine (41%). Total lymphocyte counts fell to &lt;500 cells/mm3 in 45% of patients two months after initiating therapy with a median reduction of 63% from the baseline (p&lt;0.0001). The median survival of patients with lymphocyte counts &lt;500 cells/mm3 at 2 months was 14 months versus 20 months in patients with more lymphocytes (p=0.0485). Univariate analysis revealed no significant association between pre-treatment patient characteristics and survival. Multivariate analysis revealed a significant association between survival and lymphocyte count (&lt;500 vs ≥ 500 cells/mm3) at 2 months (HR 2.2, p = 0.014). Conclusions: Adjuvant radiation and chemotherapy induced lymphopenia is frequent, severe, and an independent predictor for survival in patients with resected pancreatic adenocarcinoma. </jats:p

Abstract 1242: The association between treatment-related lymphopenia and survival in patients with solid tumors.

Abstract Background: This retrospective review was conducted to determine: 1) the frequency and severity of treatment related lymphopenia (TRL) in solid tumors, 2) its association with survival accounting for prognostic variables, and 3) its relationship to radiation or chemotherapy. Methods: Serial lymphocyte counts (pre-treatment and monthly for one year), prognostic factors, treatment details, and survival were retrospectively reviewed in 338 newly diagnosed patients with 1) high grade glioma, 2) resected pancreatic cancer, 3) unresectable pancreatic cancer, 4) stage III lung cancer, and 5) HPV- head and neck cancer in this IRB approved study. Severe TRL was defined as grade III-IV lymphopenia (&amp;lt;500 cells/mm3). Results: The findings in each patient cohort are similar: 1) About 40% of patients develop severe TRL two months after initiating radiation and this persists for many months, 2) There is an association between TRL at two months and shorter survival from tumor progression, and 3) The hazard ratio for reduced survival is high after adjusting for known prognostic factors. Lung cancer patients treated with neoadjuvant chemotherapy did not experience TRL until after radiation was initiated. Conclusions: Severe TRL is common, severe, long-lasting and associated with earlier death from tumor progression in patients with solid tumors receiving radiation and chemotherapy. These studies suggest that radiation likely plays a major role in the development of TRL and that novel approaches to protect and/or restore immunologic function in patients with solid tumors are critical. NeoplasmTotal number patientsPatients developing grade III-IV TRLMedian Survival &amp;lt;500 vs &amp;gt;500 lymphocytes (months)Multivariate association with reduced survival:HR, (CI), pvalueHigh grade glioma9640%13 vs 19.7 (p = 0.002)OS: 1.66, (1.05–2.64), 0.03Pancreatic resected5345%14 vs 20 (p = 0.048)OS: 2.2, (1.17–4.12), 0.01Pancreatic unresectable12074%9.2 vs 14.6 (p = 0.013)OS: 1.34, (0.09–2.0), 0.15NSCLC Stage III4750%21.8 vs 28.3 (p = 0.38)OS: 1.7, (0.8–3.6), 0.17HEENT (HPV)2236%PFS onlyPFS: 6.2, (1.1–35.2), 0.04 Citation Format: Stuart A. Grossman, Susannah Yovino, Jian Campian, Aaron Wild, Joseph Herman, Daniel Laheru, Malcolm Brock, Shanthi Marur, Ani Balmanoukian, Xiaobu Ye. The association between treatment-related lymphopenia and survival in patients with solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1242. doi:10.1158/1538-7445.AM2013-1242</jats:p