Stereotactic MR-Guided On-Table Adaptive Radiation Therapy (SMART) for Patients with Borderline or Locally Advanced Pancreatic Cancer: Primary Endpoint Outcomes of a Prospective Phase II Multi-Center International Trial

Retrospective studies demonstrate that ablative stereotactic MR-guided on-table adaptive radiation therapy (SMART) achieves favorable local control (LC) and overall survival (OS) with limited grade 3+ toxicity compared to historical non-ablative outcomes for locally advanced and borderline resectable pancreatic cancer (LAPC/BRPC). We conducted an international multi-center single-arm phase 2 trial of ablative 5-fraction SMART for LAPC/BRPC. Subjectswere required to have biopsy-confirmed adenocarcinoma, receive ≥3 months of chemotherapy, have no distant metastasis and CA19-9 ≤500 U/mL. SMART was delivered on a 0.35T MR-60Co or MR-linac system prescribed to 50 Gy in 5 fractions (biologically effective dose10 [BED10]=100 Gy) using continuous intrafraction cine-MRI, soft tissue tracking, and automatic beam gating. The original plan was recomputed onto the daily anatomy and if that plan would not have met constraints, on-table adaptive replanning using an isotoxicity approach was performed. The primary objective was to demonstrate <15.8% acute grade 3+ gastrointestinal (GI) toxicity definitely related to SMART measured through 90 days and evaluated according to Common Terminology Criteria for Adverse Events v5.0 (CTCAE). All patients have completed 90-day follow-up. Secondary objectives included OS, distant progression free survival (DPFS), and patient-reported quality of life. 136 patients across 13 sites were enrolled between 2019-2021. Mean age was 65.7 years. Head of pancreas lesions were most common (66.9%; n=91). 43.4% (n=59) had BRPC, 56.6% (n=77) LAPC. Mean induction chemotherapy duration was 155.7 days, typically with FOLFIRINOX 65.4% (n=89) or gemcitabine doublet 16.9% (n=23). Mean CA19-9 after induction chemotherapy was 71.7 U/mL. On-table adaptive replanning was used for 93.1% of fractions. SMART was delivered in consecutive days (56.6%) or every other day (43.4%). Median follow-up was 16.4 months and 8.8 months from diagnosis and SMART, respectively. 31.6% (n=43) had surgery after SMART. The incidence of acute grade 3+ GI toxicity definitely and probably related to SMART were 0% and 2.2% (n=3), respectively. 1-year LC and DPFS from SMART were 82.9% and 50.6%, respectively. 1-year OS was 93.9% from diagnosis and 65.0% from SMART. This is the first prospective, multi-institutional study of ablative SMART with prescribed BED10 of 100 Gy delivered in 5 fractions for BRPC/LAPC. The primary objective was met, signaling that further prospective evaluation of ablative SMART for BRPC/LAPC is warranted with a focus on long-term LC and OS compared to chemotherapy alone

Quality of Life after Ablative 5-Fraction Radiation Therapy from the Phase 2 SMART Pancreas Trial

Prospective data demonstrate that non-ablative stereotactic body radiation therapy (SBRT) for pancreas cancer is well tolerated and results in stable patient-reported quality of life (QOL) although few studies have evaluated long-term QOL beyond ∼3 months after SBRT. Ablative SBRT (BED10 ∼100 Gy) is increasingly being adopted and its effects on QOL are unknown. We now present QOL outcomes from a phase 2 trial evaluating ablative 5-fraction stereotactic MR-guided on-table adaptive radiation therapy (SMART) for borderline resectable and locally advanced pancreas cancer. The multi-center single-arm phase 2 SMART trial enrolled 136 patients from January 2019 to January 2022 who received ≥3 months of induction chemotherapy without disease progression and were treated on a 0.35T MR-guided device with a prescribed dose of 50 Gy in 5 fractions (BED10 = 100 Gy). Intrafraction cine-MRI, soft tissue tracking, and automatic beam gating were mandatory. On-table adaptive replanning using an isotoxicity approach was performed prior to each fraction as needed. A secondary study endpoint was QOL using the NCCN-FACT FHSI-18 survey instrument at 3 times (T): prior to SMART (T1), 3 months after SMART (T2), and 12 months after SMART (T3). The total FHSI-18 score was calculated as a sum of the following subscale scores: disease related symptoms-physical, disease related symptoms-emotional, treatment side effects, and function/well-being. Surgery was performed in 44 patients (32.4%) after SMART. QOL assessment was completed at T1, T2, and T3 by 133 (97.8%) and 106 (77.9%), and 55 (40.4%) patients, respectively. Mean total score and subscale scores remained stable from T1-T2 or T1-T3. Mean individual question scores were stable from T1-T2 except for general pain (0.8 vs. 1.1; p=0.002) and localized stomach pain (1.0 vs. 1.3; p=0.013); a significant increase in pain scores was present among patients who had surgery after SMART while pain scores did not increase among those who did not have surgery. Mean individual scores were stable from T1-T3 except for increased stomach area pain (p<0.001) regardless of surgery and scores for feeling ill increased among patients who did not have surgery (p=0.004). This is the first prospective evaluation of QOL after ablative radiation therapy for pancreas cancer demonstrating that overall QOL remains stable at 3 and 12 months after SMART. Additional analysis is warranted to clarify factors significantly associated with QOL including disease progression and additional therapy after SMART

Autophagy Promotes Immune Evasion of Pancreatic Cancer by Degrading MHC-I

Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy1-3. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found5 despite the frequent downregulation of MHC-I expression6-8. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC