An In Situ Patient-specific Chemo-Immunotherapy for Skin Cancers

该项目将评估一种全新的皮肤癌治疗方法，适用于广泛的局部皮肤癌。我们提出共同递送有效的化疗剂和免疫修饰剂以杀死局部可接近的癌细胞，同时将皮肤肿瘤转化为能够诱导先天性、适应性和肿瘤特异性记忆免疫应答的高效患者特异性免疫原。该策略是由我们实验室开发和生产的独特的微针阵列（MNA）输送装置实现的。治疗方法是多功能和协同的。化疗和辅助治疗在时间和空间上相结合。化疗是用来杀死现有的肿瘤细胞，通过免疫原性的“良好的死亡”机制，将垂死的细胞转化为丰富的肿瘤抗原来源。同时，将有效的佐剂递送至肿瘤床以募集和激活先天免疫应答和抗原呈递细胞。这种联合治疗预期导致化疗和免疫介导的肿瘤溶解，在促免疫原性环境中提供全长自体肿瘤抗原的丰富来源，这将促进抗原性广泛的肿瘤特异性细胞和体液免疫的发展。该方法具有通过直接利用患者的肿瘤作为免疫原的来源而提供患者和肿瘤特异性免疫的额外优点，从而消除了与抗原和肿瘤异质性相关的障碍。我们开发的可溶性MNAs可以同时将化疗剂和免疫佐剂递送到相同的皮肤微环境，从而能够通过低剂量递送来操纵肿瘤微环境，几乎没有全身暴露或毒性。此外，装载到MNA设备中的生物活性货物非常稳定，并且消除了对冷链的依赖。与易于制造和最小剂量一起，这些特征使得经济上可行的患者特异性化学免疫成为可能。 在这个项目中，我们将测试我们的假设，即原位局部MNA导向的化学免疫疗法将局部杀死肿瘤细胞，并改变肿瘤微环境，以诱导持久的全身肿瘤特异性免疫。在这方面，该策略的第一次临床应用，我们的目标是通过I/II期临床试验评估在患有在途黑素瘤的患者和CTCL患者中的MNA导向的化学免疫疗法。我们将评价局部和全身的临床反应和治疗诱导的免疫效应。

This project will evaluate an entirely novel approach to skin cancer treatment applicable to a broad range of topically accessible skin cancers. We propose to co-deliver a potent chemotherapeutic agent and an immune modifier to kill topically accessible cancer cells and simultaneously convert a cutaneous neoplasm into a highly potent patient specific immunogen capable of inducing innate, adaptive, and tumor specific memory immune responses. The strategy is enabled by a unique microneedle array (MNA) delivery device developed and produced in our laboratory. The therapeutic approach is polyfunctional and synergistic. Chemotherapy and adjuvant therapy are combined temporally and spatially. Chemotherapy is used to kill existing tumor cells through immunogenic "good death" mechanisms that convert dying cells into a rich source of tumor antigen. Simultaneously, a potent adjuvant is delivered to the tumor bed to recruit and activate innate immune responses and antigen presenting cells. This combined therapy is expected to result in both chemotherapeutic and immune-mediated tumor lysis, providing a rich source of full-length autologous tumor antigens in a pro-immunogenic environment that will promote the development of antigenically broad tumor-specific cellular and humoral immunity. This approach has the additional advantage of affording patient and tumor specific immunity by utilizing the patient's tumor directly as a source of immunogen, obviating obstacles related to antigen and tumor heterogeneity. The dissolvable MNAs we have developed can simultaneously deliver chemotherapeutic agent(s) and immune adjuvant(s) to the same cutaneous microenvironment, enabling manipulation of the tumor microenvironment through low dose delivery, with virtually no systemic exposure or toxicity. Further, the biologically active cargos loaded into MNA devices are extremely stable, and eliminate dependency on the cold chain. Together with the ease of fabrication and minimal dosing, these features enable an economically feasible patient specific chemo-immunization. In this project, we will test our hypothesis that in situ topical MNA-directed chemo-immunotherapy will kill tumor cells locally and alter the tumor microenvironment to induce durable systemic tumor specific immunity. In this, the first clinical application of this strategy, our goal is to evaluate MNA-directed chemoimmunotherapy in patients with in-transit melanoma and in CTCL patients through phase l/ll clinical trials. We will evaluate clinical responses and therapy induced immune effects locally and systemically.