Controlled-release particulate cytokine adjuvants for cancer therapy
Controlled-release particulate cytokine adjuvants for cancer therapy
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DOI：
10.2174/187153007782794335
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发表时间：
2007-12-01
影响因子：
1.9
通讯作者：
Conway, Thomas F.
中科院分区：
文献类型：
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作者：
Egilmez, Nejat K.;Kilinc, Mehmet O.;Conway, Thomas F.
细胞因子治疗可以诱导癌症患者的肿瘤消退，但全身给予细胞因子伴随严重的毒性。局部区域给药是全身注射的一种有效且毒性较小的替代方法。然而，需要频繁重复注射重组细胞因子或与基因修饰相关的后勤困难限制了局部区域治疗的广泛应用。一种更简单的替代局部递送策略涉及使用控释细胞因子储库制剂。这些制剂提供的优点是，生理剂量的细胞因子以持续的方式直接释放到肿瘤微环境中。已在同基因鼠和人肿瘤/SCID小鼠异种移植物模型中评价了IL-2、IL-12、GM-CSF或TNF α包封的聚合物微球的抗肿瘤功效。这些制剂的单次肿瘤内注射;特别是IL-12与GM-CSF或TNF α的组合;促进了已建立的原发性肿瘤的消退，诱导了全身性抗肿瘤T细胞和NK细胞应答，并实现了播散性疾病的完全根除。对治疗后肿瘤微环境的细胞和分子分析表明，治疗促进了肿瘤相关T效应/记忆细胞的活化; CD4 + CD25 + Foxp3 + T抑制因子的消除和肿瘤特异性CD8 + T效应细胞的从头启动。对治疗后肿瘤的长期监测表明，肿瘤内免疫抑制的逆转是短暂的，并且T抑制细胞迅速重新浸润肿瘤。重复治疗恢复了抗肿瘤活性;然而，治疗效果随着每个治疗周期而下降。观察到的疗效丧失与治疗后T抑制细胞反弹的进行性强化相关。与此相反;在每个治疗周期之前用低剂量化疗耗尽T-抑制细胞导致长期治疗功效的显著增强，从而导致完全缓解。本文讨论了这些发现的临床意义。
Cytokine therapy can induce tumor regression in cancer patients but systemic administration of cytokines is accompanied with severe toxicity. Loco-regional delivery represents an effective and less toxic alternative to systemic injection. However; the requirement for frequent repeated injections of recombinant cytokine or the logistical difficulties associated with gene- modification have limited wide-spread use of loco-regional therapy. A simpler alternative local delivery strategy involves the use of controlled-release cytokine depot formulations. These formulations provide the advantage that physiological doses of cytokines are directly released to the tumor microenvironment in a sustained manner. Anti-tumor efficacy of IL-2; IL-12; GM-CSF or TNF alpha-encapsulated polymer microspheres has been evaluated in syngeneic murine and human tumor /SCID mouse xenograft models. A single intra-tumoral injection of these formulations; particularly that of IL-12 in combination with GM-CSF or TNF alpha; promoted the regression of established primary tumors-, induced systemic anti-tumor T- and NK-cell responses and achieved complete eradication of disseminated disease. Cellular and molecular analysis of post-therapy tumor microenvironment demonstrated that treatment promoted the activation of tumorassociated T-effector/memory cells; the elimination of CD4+ CD25+ Foxp3+ T-suppressors and the de novo priming of tumor-specific CD8+ T-effector cells. Long-term monitoring of post-therapy tumors revealed that reversal of intra-tumoral immune suppression was transient and that T-suppressor cells rapidly re-infiltrated tumors. Repeated treatment resurrected anti-tumor activity; however, therapeutic efficacy declined with each treatment cycle. The observed loss of therapeutic efficacy was associated with a progressive intensification of the post-treatment T-suppressor cell rebound. In contrast; depletion of T-suppressor cells with low dose chemotherapy prior to each cycle of treatment resulted in a dramatic enhancement of long-term therapeutic efficacy leading to complete remissions. Clinical implications of these findings are discussed herein.