Phase II Clinical Trial of Intratumoral Dendritic Cells Injections and Neoadjuvant Radiotherapy in Resectable Soft Tissue Sarcomas

Shailaja Raj MD; Gregory Springett MD PhD, Daniel Indelicato MD, Marilyn Bui MD PhD, Anthony Conley MD, Sergio Lavilla-Alonso PhD, Xiuhua Zhao MS, Dungsa Chen PhD, Randy Haysek MD, Ricardo Gonzalez MD, Douglas Letson MD, Steven Eric Finkelstein MD PhD, Alberto Chiappori MD, Dimitry Gabrilovitch MD PhD, Scott J Antonia MD PhD
Published: Wednesday, Feb 21, 2018
Shailaja Raj MD
Shailaja Raj, MD

Abstract

Purpose: Dendritic cell (DC) vaccines are anticipated as a treatment regimen for the future in the management of solid tumors. Previously we have shown that DC-based vaccines show a consistent immune response, safety, and long-term survival with neoadjuvant radiation.

Methods: Patients (N = 14) were assigned to neoadjuvant 50 Gy of external beam radiation (EBRT), given in 25 fractions delivered 5 days/week, combined with 4 intratumoral injections of DCs, followed by complete resection. The control arm consisted of 6 patients treated with just neoadjuvant radiation followed by surgery. The primary endpoint was to establish safety and efficacy of the vaccine with immunological correlation.

Results: Median follow-up was 30 months. The primary endpoint of demonstrating the safety of the DC vaccine was achieved, but clinical efficacy with immunological correlation was not statistically significant. Eleven out of fourteen (66.6%) patients on the DC vaccine arm were alive, of which 8/14(57%) had no systemic recurrences over a period of 4 years. Favorable immunological responses correlated with clinical responses in some cases.

Conclusions: Neoadjuvant radiation with dendritic cell injections has the potential to be safe, effective, and immunogenic in high-grade soft tissue sarcoma and needs to be confirmed in randomized larger clinical trials.

Introduction

Tumor heterogeneity, high grade, and larger tumors portend a poor prognosis in soft tissue sarcomas.1,2 In particular chemotherapy, radiation, and surgery, have not succeeded in establishing remission in these patients where comorbidities and older age may be risk factors as well.3,4,5,6,7,8 Therefore, tumor vaccines may be ideal in this population due to their favorable toxicity profile.

Investigations in immunology have developed several tumor-vaccine, antigen vaccine, and dendritic cell (DC)-vaccine strategies.9 In preliminary studies using animal tumor models, we tested the hypothesis that a combination of apoptosis-inducing therapy with intratumoral administration of DCs can result in a potent antitumor response. We used mouse models to prove the concepts that, after tumor irradiation, injected DCs migrate to the tumor site, induce an antitumor immune response after engulfing tumor cells.10

Our group had also studied the systemic immune response of hypo-fractionated high-dose RT in metastatic breast cancer subjects and evaluated the tumor-specific RT-induced autoantibody (RIAA) formation. The 3-year overall survival in IgM or IgG positive patients were significantly superior to those in the negative group, and there were no significant disparities in subject and treatment characteristics between these two groups to account for differences in outcome. Greater than half of our subjects demonstrated the formation of RIAA, considering that those who were included had previously received multiple immunosuppressive chemotherapeutic regimens. Importantly, those patients who exhibited RIAA had a prolonged interval before developing new metastatic lesions, and RIAA formation conferred superior survival outcomes. Radioimmunoassay experiments defined potential immunomodulatory mechanisms leading to RIAA formation to detect differences in cytokine levels in those patients who mounted an antibody response. All patients with GM-CSF, IFN-γ or TNF-α, enjoyed an immune response suggesting an interaction between radiation therapy (RT) immunologic signaling and these cytokines. Our observations were compelling for the assertion that hypofractionated RT can induce tumor-specific autoimmunity. This autoimmunity works synergistically with the local tumor-killing effects of RT, and ultimately, translates into an improvement in survival.

Survivin, a member of the inhibitor-of-apoptosis IAP gene family, is correlated with tumor progression and poor prognosis.11,12,13 It has a strong potential as a tumor marker for solid tumors of mesodermal origin.14,15 Survivin is also correlated with poor survival in tumor types, like breast, glioma, lymphoma, and colorectal cancers. Our group had previously developed an experimental system to measure survivin-specific immune responses in healthy individuals and prostate-cancer patients in which it demonstrated that survivin-specific immune responses can be rated and detected in vitro.17,18 Previously, studies have also shown a highly increased risk of tumor-related death in a group of soft tissue sarcomas (STS)patients who demonstrated a significant correlation between the co-expression of the survivin mRNA and the telomerase reverse transcriptase mRNA. Prognostic information of STS can be obtained from ELISA that is adapted for survivin content measurement in cell lysates and tissue extracts.14


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