Clinical Investigation
Combination of External Beam Radiotherapy (EBRT) With Intratumoral Injection of Dendritic Cells as Neo-Adjuvant Treatment of High-Risk Soft Tissue Sarcoma Patients

This work was presented at the 51st ASTRO meeting and was awarded clinical winner of the resident clinical/basic science research award.
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Purpose

The goal of this study was to determine the effect of combination of intratumoral administration of dendritic cells (DC) and fractionated external beam radiation (EBRT) on tumor-specific immune responses in patients with soft-tissue sarcoma (STS).

Methods and Material

Seventeen patients with large (>5 cm) high-grade STS were enrolled in the study. They were treated in the neoadjuvant setting with 5,040 cGy of EBRT, split into 28 fractions and delivered 5 days per week, combined with intratumoral injection of 107 DCs followed by complete resection. DCs were injected on the second, third, and fourth Friday of the treatment cycle. Clinical evaluation and immunological assessments were performed.

Results

The treatment was well tolerated. No patient had tumor-specific immune responses before combined EBRT/DC therapy; 9 patients (52.9%) developed tumor-specific immune responses, which lasted from 11 to 42 weeks. Twelve of 17 patients (70.6%) were progression free after 1 year. Treatment caused a dramatic accumulation of T cells in the tumor. The presence of CD4+ T cells in the tumor positively correlated with tumor-specific immune responses that developed following combined therapy. Accumulation of myeloid-derived suppressor cells but not regulatory T cells negatively correlated with the development of tumor-specific immune responses. Experiments with 111In labeled DCs demonstrated that these antigen presenting cells need at least 48 h to start migrating from tumor site.

Conclusions

Combination of intratumoral DC administration with EBRT was safe and resulted in induction of antitumor immune responses. This suggests that this therapy is promising and needs further testing in clinical trials design to assess clinical efficacy.

Introduction

Intratumoral administration of dendritic cells (DC) is one of the promising methods of induction of therapeutic antitumor immune responses. The main advantage of this approach is that a large variety of tumor-associated antigens present in tumors can be used. In addition, patients do not need to be selected or excluded based on human leukocyte antigen (HLA) type or the expression of specific antigens. However, immunotherapy alone rarely causes curative antitumor effects as the manipulation of tumor microenvironment is necessary to potentiate the effect of DC administration (1). Ionizing radiation presents one such powerful intervention. Radiation can not only kill tumor cells releasing tumor antigens, but can also exert various immunomodulatory effects including induction of the expression of cytokines, chemokines, and release of inflammatory mediators 2, 3, 4. It also increases the permeability of the local vasculature that leads to re-cruitment of circulating leukocytes into surrounding tissues including antigen-presenting cells and effector T cells 5, 6, 7. Thus, the proinflammatory microenvironment within irradiated tumors could provide DCs with maturation-inducing stimuli critical for eliciting effective antigen presentation.

We and others have demonstrated in preclinical studies that local tumor irradiation in combination with intratumoral DC administration but not irradiation alone resulted in potent antitumor immune responses that translated into an antitumor effect 7, 8, 9, 10, 11, 12. These preclinical studies provided a compelling rationale for testing this approach in the clinic. In a Phase I clinical trial of hepatoma, intratumoral administration of DCs in combination with a single high dose of conformal radiation was found to be safe and in some cases resulted in induction of tumor-specific immune responses 13, 14. However, it remains unclear whether conventionally fractionated external beam radiotherapy (EBRT) coupled with DC can cause a robust immune response in a substantial proportion of patients, whether this response correlates with clinical outcome, and whether the treatment affects immune suppressive cells present in cancer patients. In this study, we tested this approach in patients with soft-tissue sarcomas (STS).

Sarcomas are relatively rare neoplasms with approximately 10,000+ new cases occurring in the United States every year. Many studies have shown that the preoperative radiotherapy and surgery is an effective strategy to treat many STS with high-risk features 15, 16, 17, 18. Unfortunately, conventional therapy for large, high-grade tumors is frequently systemically ineffective, which makes this a very deadly problem. Indeed, despite a multidisciplinary, multimodality approach employing radiation therapy and at times systemic chemotherapy, approximately 50% of patients with large, high-grade STS will go on to develop distant metastasis (19). Novel approaches to deal with the systemic potential of this disease are needed.

Section snippets

Patient selection and treatment

Seventeen patients with histologically confirmed large high-grade STS of the extremity/trunk/chest wall were enrolled to the study (Table 1). These patients had clinical stage T2N0M0 with a significant (>50%) risk of progressing to distant metastases. All patients provided written informed consent to an Institutional Review Board of University of South Florida approved protocol. Treatment schema is shown in Fig. S1. Patients were treated with EBRT combined with experimental intratumoral

Clinical response to combination of EBRT with intratumoral DC administration

No significant (≥Grade 2) toxicity was observed during combination EBRT/DC neoadjuvant treatment. Postoperative wound complications were observed in 5/17 patients (29.41%) defined using NCIC criteria (16). Twelve patients (70.6%) had no evidence of the disease for at least one year after the start of the treatment (time of follow-up). Among those 12 patients, 6 are disease-free for more than 2 years and 4 patients for more than 3 years. There were no local recurrences. Pathological evaluation

Discussion

We report the clinical and immunologic results of the first Phase I/II trial in humans combining localized fractionated EBRT with intratumoral administration of DCs in patients afflicted with high-risk STS. Treatment was well tolerated by all patients. The frequency of wound complications (29.1%) was similar to that reported for EBRT alone 16, 28. The proportion of patients remaining disease free 1 year after the treatment (70.6%) was similar to that reported for patients with high-grade, large

Acknowledgments

This manuscript is dedicated in memory of Erin Bryant, our nurse, colleague, and friend.

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    This work was supported by grant from “Gateway for Cancer Research” (to D.I.G.).

    S.E.F., C.I., and M.M.B. contributed equally to this work.

    Conflict of interest: none

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