No abstract

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA–lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.

A 67-year-old right-handed woman presented with dysarthria, left upper extremity weakness and right-sided neglect of 3 hours duration. Imaging of the brain revealed acute right middle cerebral artery stroke; however, tissue plasminogen activator could not be administered due to severe thrombocytopenia. A peripheral smear revealed schistocytes and the patient was treated empirically for thrombotic thrombocytopenic purpura (TTP) with therapeutic plasma exchange. An extensive workup revealed no embolic source or other cause for stroke, and a diagnosis of large vessel infarct secondary to TTP was made. After a prolonged hospital course, the patient had partial neurological recovery and was discharged to a rehabilitation facility. Although transient neurologic deficits due to small vessel occlusions are well described in TTP, large vessel infarct can occur as well. This diagnosis should be considered in patients presenting with concomitant stroke and thrombocytopenia, as untreated TTP is nearly always fatal.

226 Background: Based on the positive results of the CALGB 80803 study (J Clin Oncol 2017;35:1 [abstr]), we have added D to induction FOLFOX and pre-op CRT. Methods: Patients (Pts) had TanyN+ or T3-4NanyM0 esophageal and Siewert Type I-III GEJ adenocarcinoma staged by EUS, PET/CT and CT. Pts received mFOLFOX6 ×2 prior to repeat PET/CT. PET responders (PETr) received 5-FU or capecitabine and oxaliplatin with RT to 50.4Gy, while induction PET non-responders (PETnr) received carboplatin/paclitaxel with RT. All Pts received D 1,500 mg q4W ×2 starting 2 wks prior to and during CRT. Esophagectomy was planned 6-8 weeks after CRT. Pts who had R0 resections received adjuvant D 1,500mg q4W ×6. Results: 36 Pts have been enrolled: 25 GEJ, 11 esophageal; 23 N+ and 32 T3/4. 26 of 36 Pts (72%) are PETr. 2 Pts developed metastatic disease after CRT and 9 Pts remain on preop treatment. 25 Pts have had surgery (Table). Pathologic complete response (pCR) was seen in 6 (24%); 5 Pts (20%) had ypT1N0 tumors with 99% response and 2 Pts (8%) had ypT0N1 with 99% response. 20 Pts (80%) had >90% response. 3 Pts had MSI tumors (2 PETr; 1 pCR, 1 T1aN0 99% response, 1 ypT2N0 90% response). Notable grade (gd) 3/4 adverse events (AEs) observed were neutropenia in 8 Pts (22%), diarrhea and vomiting in 2 Pts each (6%). Notable gd 1/2 AEs in ≥20%: anemia (31 Pts), thrombocytopenia (29 Pts), nausea (21 Pts), fatigue (25 Pts), increased AST (20 Pts), constipation and diarrhea (9 Pts), diarrhea (8 Pts). Immune-related AEs noted were gd 2 dermatitis (2 Pts), gd 3 hepatitis and gd 1 hypothyroidism in 1 Pt each. Median length of post-op stay was 8 days, with 12% anastomotic complication rate, including 1 Pt who died of hematemesis 16 days after discharge from 55-day hospitalization. Conclusions: The addition of D to induction FOLFOX and PET-directed CRT is safe and feasible. pCR and near-pCR in ½ of operated Pts is encouraging and compares favorably to the pCR rate of 31% in CALGB 80803 Pts who received induction FOLFOX. The final pCR rate and correlatives for the fully accrued study will be presented. Clinical trial information: NCT02962063. [Table: see text]

16 Background: Total neoadjuvant therapy with induction chemotherapy and chemoradiation (chemoRT) is the standard treatment for locally advanced rectal adenocarcinomas. Mismatch repair deficient (dMMR) rectal tumors respond poorly to neoadjuvant chemotherapy. PD-1 blockade is effective in patients with metastatic dMMR colorectal cancers, but its efficacy has not been established in the neoadjuvant setting. The purpose of this study is to evaluate the clinical benefit of neoadjuvant PD-1 blockade in dMMR locally advanced rectal cancer. Methods: We designed a prospective, single-arm, phase II study in which patients with stage II and III dMMR rectal cancer receive neoadjuvant dostarlimab (anti-PD-1) for a total of 6 months. The co-primary objectives are to determine the overall response rate (ORR) and pathologic complete response (pCR) or clinical complete response rate (cCR) with or without chemoRT. Tumor assessment with endoscopic evaluation is performed at baseline, 6 weeks, 3 months and 6 months; imaging is performed at pretreatment baseline, 3 months and 6 months. Patients with cCR by previously established criteria are eligible for non-operative management without chemoRT. Those with residual disease after neoadjuvant dostarlimab receive standard chemoRT. Following chemoRT, any patient failing to achieve a cCR is then managed surgically. Results: A total of 13 patients have been enrolled, with median age 52 years (range 26-78), 77% female, and 92% with node-positive disease by rectal MRI. The ORR is 100% in the 12 patients who have undergone at least a 3-month evaluation. Seven patients have completed induction therapy and all 7 (100%) have achieved a cCR and are undergoing observation without chemoRT or surgery. The rate of progressive disease thus far is 0%. No patients have required chemoRT or surgery. There have been no serious adverse events. Conclusions: Single agent neoadjuvant PD-1 blockade with dostarlimab is effective and well-tolerated in locally advanced dMMR rectal adenocarcinoma and allows patients to avoid chemoradiation and surgery. This suggests a potential new paradigm for treatment of dMMR locally advanced rectal cancer. Follow up and further patient accrual is ongoing. Clinical trial information: NCT04165772.