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BackgroundNeoantigen (NeoAg) peptides displayed at the tumor cell surface by human leukocyte antigen molecules show exquisite tumor specificity and can elicit T cell mediated tumor rejection. However, few NeoAgs are predicted to be shared between patients, and none to date have demonstrated therapeutic value in the context of vaccination.MethodsWe report here a phase I trial of personalized NeoAg peptide vaccination (PPV) of 24 stage III/IV non-small cell lung cancer (NSCLC) patients who had previously progressed following multiple conventional therapies, including surgery, radiation, chemotherapy, and tyrosine kinase inhibitors (TKIs). Primary endpoints of the trial evaluated feasibility, tolerability, and safety of the personalized vaccination approach, and secondary trial endpoints assessed tumor-specific immune reactivity and clinical responses. Of the 16 patients with epidermal growth factor receptor (EGFR) mutations, nine continued TKI therapy concurrent with PPV and seven patients received PPV alone.ResultsOut of 29 patients enrolled in the trial, 24 were immunized with personalized NeoAg peptides. Aside from transient rash, fatigue and/or fever observed in three patients, no other treatment-related adverse events were observed. Median progression-free survival and overall survival of the 24 vaccinated patients were 6.0 and 8.9 months, respectively. Within 3–4 months following initiation of PPV, seven RECIST-based objective clinical responses including one complete response were observed. Notably, all seven clinical responders had EGFR-mutated tumors, including four patients that had continued TKI therapy concurrently with PPV. Immune monitoring showed that five of the seven responding patients demonstrated vaccine-induced T cell responses against EGFR NeoAg peptides. Furthermore, two highly shared EGFR mutations (L858R and T790M) were shown to be immunogenic in four of the responding patients, all of whom demonstrated increases in peripheral blood neoantigen-specific CD8+ T cell frequencies during the course of PPV.ConclusionsThese results show that personalized NeoAg vaccination is feasible and safe for advanced-stage NSCLC patients. The clinical and immune responses observed following PPV suggest that EGFR mutations constitute shared, immunogenic neoantigens with promising immunotherapeutic potential for large subsets of NSCLC patients. Furthermore, PPV with concurrent EGFR inhibitor therapy was well tolerated and may have contributed to the induction of PPV-induced T cell responses.

BackgroundThe adoptive transfer of tumor-infiltrating lymphocytes (TIL) has demonstrated robust efficacy in metastatic melanoma patients. Tumor antigen–loaded dendritic cells (DCs) are believed to optimally activate antigen-specific T lymphocytes. We hypothesized that the combined transfer of TIL, containing a melanoma antigen recognized by T cells 1 (MART-1) specific population, with MART-1-pulsed DC will result in enhanced proliferation and prolonged survival of transferred MART-1 specific T cells in vivo ultimately leading to improved clinical responses.DesignWe tested the combination of TIL and DC in a phase II clinical trial of patients with advanced stage IV melanoma. HLA-A0201 patients whose early TIL cultures demonstrated reactivity to MART-1 peptide were randomly assigned to receive TIL alone or TIL +DC pulsed with MART-1 peptide. The primary endpoint was to evaluate the persistence of MART-1 TIL in the two arms. Secondary endpoints were to evaluate clinical response and survival.ResultsTen patients were given TIL alone while eight patients received TIL+DC vaccine. Infused MART-1 reactive CD8+ TIL were tracked in the blood over time by flow cytometry and results show good persistence in both arms, with no difference in the persistence of MART-1 between the two arms. The objective response rate was 30% (3/10) in the TIL arm and 50% (4/8) in the TIL+DC arm. All treatments were well tolerated.ConclusionsThe combination of TIL +DC showed no difference in the persistence of MART-1 TIL compared with TIL therapy alone. Although more patients showed a clinical response to TIL+DC therapy, this study was not powered to resolve differences between groups.Trial registration numberNCT00338377.

Background Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) has shown great benefit in patients with melanoma.1,2 It was suggested that long term tumor immunosurveillance is provided by TIL persisting after transfer. Dendritic cells (DC) are professional antigen presenting cells and have the ability to optimally activate T lymphocytes.3 We hypothesized that the combination of autologous TIL containing a population of HLA-A0201 restricted MART-1 reactive CD8+ TIL with autologous MART-1 antigen-pulsed DCs will result in enhanced proliferation and prolonged survival of the transferred antigen-specific T cells in vivo, thus leading to improved clinical responses. Methods This is a randomized phase II trial of lymphodepleting chemotherapy followed by autologous TILs ± DC vaccine and high dose Interleukin-2 (IL-2) for patients with metastatic melanoma. Patients were randomized to receive TIL alone or TIL + DCs pulsed with MART-1 peptide. The primary objective was to determine whether patients receiving TIL + DCs have sustained persistence of infused T cells compared to patients treated with TIL alone. Secondary endpoints included evaluation of tumor response and survival. Results A total of 18 patients with stage IV melanoma were treated; 89% with stage M1c, including 56% with brain metastasis; 17% had high LDH level. All but one patient were checkpoint naive prior to TIL. Ten patients received TIL alone and eight received TIL + DC. Treatments were well tolerated with no grade 5 adverse events. There were no toxicities conferred by the DC vaccination. The ORR was 63% (5/8) in TIL + DC arm (1 CR, 4 PR) and 40% (4/10) in TIL arm alone (1 CR, 3 PR) (P=0.64). There was no statistically significant difference in survival between the arms. The median progression-free survival (PFS) was 3.6 months in the TIL arm and 7.2 months in the TIL+DC arm, while the median overall survival (OS) was 4.1 years in the TIL arm and 2 years in the TIL+DC arm. Tracking of the infused MART-1 reactive CD8+ T cells in the blood over time by flow cytometry showed no difference in persistence between the two arms. Conclusions ACT with TILs has robust response in checkpoint naive advanced melanoma patients. Despite numerically higher response rate in the TIL+DC arm, due to small patient number there was no statistically significant difference between the arms. Further testing of this approach in a prospective trial post-ICI is warranted. Trial Registration All metastatic melanoma TIL lines were derived from tumor tissue obtained from patients enrolled on the TIL ACT clinical trial [institutional review board (IRB)-approved protocol# 2004-0069, NCT00338377] at The University of Texas MD Anderson Cancer Center. Ethics Approval The United States Food and Drug Administration and the Institutional Review Board at MD Anderson Cancer Center approved the study. This study was conducted according to the principles from the Declaration of Helsinki. Consent All study participants granted a written informed consent prior to treatment initiation. References Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015;348(6230):62–8. Forget MA, Haymaker C, Hess KR, Meng YJ, Creasy C, Karpinets T, et al. Prospective Analysis of Adoptive TIL Therapy in Patients with Metastatic Melanoma: Response, Impact of Anti-CTLA4, and Biomarkers to Predict Clinical Outcome. Clin Cancer Res. 2018;24(18):4416–28. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–52.