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有效載荷傳遞：改造免疫細(xì)胞以破壞腫瘤微環(huán)境

發(fā)表日期：2022-01-04

Payload Delivery: Engineering Immune Cells to Disrupt the Tumour Microenvironment

有效載荷傳遞：改造免疫細(xì)胞以破壞腫瘤微環(huán)境

Cell-based therapies composed of genetically engineered immune cells have huge potential for treating cancer. T cells modified to express tumour-targeting receptors have been proven to be highly effective against blood cancers but not solid malignancies. Using innovative genetic modifications, we have the potential to enhance solid tumour targeting by cell-based therapies and fulfil this unmet clinical need. Different genetic engineering approaches have been proposed, each designed to overcome specific hurdles associated with solid tumours. In this review, we discuss the novel ways of engineering immune cells to enhance efficacy against solid tumours, and how this has led to a new era of cell-based therapies, capable of delivering immunotherapeutic payloads that disrupt the immunosuppressive tumour microenvironment and generate concerted anti-tumour immune responses.

由基因工程免疫細(xì)胞組成的基于細(xì)胞的療法在治療癌癥方面具有巨大的潛力。經(jīng)修飾以表達(dá)腫瘤靶向受體的 T 細(xì)胞已被證明對血癌非常有效，但對實(shí)體惡性腫瘤無效。使用創(chuàng)新的基因修飾，我們有可能通過基于細(xì)胞的療法增強(qiáng)實(shí)體瘤的靶向性，并滿足這一未滿足的臨床需求。已經(jīng)提出了不同的基因工程方法，每種方法都旨在克服與實(shí)體瘤相關(guān)的特定障礙。

高效搖瓶

Over the past decade, we have seen huge advances in the use of cell-based therapies for the treatment of cancer. Whereas previously cell-based therapies were limited to using non-engineered cells, which would struggle to survive beyond in vitro expansion and rapidly succumb to the immunosuppressive effects of the tumour in vivo, we now have the technology to engineer immune cells with selected genes that markedly bolster their effector function in vivo and counteract the adverse conditions of the TME. Moreover, we can create polycistronic constructs capable of stably transducing a cell with multiple genes simultaneously, providing a continuous supply of natural and/or recombinant gene products for optimal performance.

In addition, approaches to engineering immune cells for adoptive cell therapy are advancing beyond just membrane-bound cytotoxicity receptors that only enhance the tumour targeting capacity of the cells that express it, and more towards secretable immunotherapy payloads, including effector cell engagers, checkpoint blocking antibodies, survival promoting cytokines, and immune orchestrating cytokines. This new wave of adoptive cell therapy uses immune cells as tumour homing cargo vessels for the targeted delivery of both membrane-bound and secretable immunotherapeutic agents directly into the TME. Importantly, these cells are no longer confined by direct cell–cell contact and can elicit their effects at range, disrupting the immunosuppressive cocoon of the tumour and converting it into a pro-immunogenic environment for anti-tumour immune cells to thrive, thus generating an orchestrated immune response against the tumour.

Although the majority of research in this field has focussed primarily on armouring αβ T cells, many of the engineering concepts described in this review are applicable to other immune chassis. Non-alloreactive cytotoxic effector cells such as NK cells and γδ T cells are currently being developed as a platform for “off-the-shelf” engineered cell-based products [139,140,141,142,143]. Furthermore, the potential to express CARs in macrophages and B cells has also been tested, exploiting alternative immune cells that function in antigen presentation, phagocytosis, and antibody production [144,145,146].

Through the co-expression of certain genes in the appropriate immune cell chassis, there is potential to disrupt the TME and improve the overall efficacy of cell-based therapies against solid malignancies. Although huge advances have been made, we have yet to see whether these approaches are effective in the clinic and many substantial hurdles still remain; in particular, current state-of-the-art engineering vectors and GMP-compliant large-scale manufacture of transduced cells for adoptive transfer present ongoing technical and financial challenges. More importantly, the rare but life-threatening toxicities associated with side effects such as cytokine release syndrome and on-target off-tumour cytotoxicity pose an underlying safety concern. Furthermore, technologies such as CARs and BiTEs are highly dependent on tumour antigen expression and thus can be blunted by the phenomena of antigen loss often associated with solid tumours. Downregulation of MHC class I expression and outgrowth of antigen low/negative malignant cells following immune selection pressure remain important limitations in this field and areas of ongoing research.

在過去的十年中，我們已經(jīng)看到使用基于細(xì)胞的療法治療癌癥的巨大進(jìn)步。以前基于細(xì)胞的療法僅限于使用非工程細(xì)胞，這些細(xì)胞將難以在體外擴(kuò)增后存活并在體內(nèi)迅速屈服于腫瘤的免疫抑制作用，而我們現(xiàn)在擁有利用選定基因設(shè)計(jì)免疫細(xì)胞的技術(shù)顯著增強(qiáng)其體內(nèi)效應(yīng)器功能并抵消 TME 的不利條件。此外，我們可以創(chuàng)建多順反子構(gòu)建體，能夠同時穩(wěn)定地轉(zhuǎn)導(dǎo)具有多個基因的細(xì)胞，提供持續(xù)供應(yīng)的天然和/或重組基因產(chǎn)品以獲得最佳性能。

此外，為過繼細(xì)胞療法設(shè)計(jì)免疫細(xì)胞的方法正在超越僅能增強(qiáng)表達(dá)它的細(xì)胞的腫瘤靶向能力的膜結(jié)合細(xì)胞毒性受體，而是更多地朝著可分泌的免疫療法有效載荷發(fā)展，包括效應(yīng)細(xì)胞接合劑、檢查點(diǎn)阻斷抗體、促進(jìn)存活的細(xì)胞因子和免疫協(xié)調(diào)細(xì)胞因子。這一新的過繼細(xì)胞治療浪潮使用免疫細(xì)胞作為腫瘤歸巢貨船，將膜結(jié)合和可分泌的免疫治療劑直接靶向遞送至 TME。重要的是，這些細(xì)胞不再受細(xì)胞與細(xì)胞直接接觸的限制，可以在一定范圍內(nèi)引發(fā)它們的影響，

10層細(xì)胞工廠

盡管該領(lǐng)域的大部分研究主要集中在裝甲 αβ T 細(xì)胞上，但本綜述中描述的許多工程概念也適用于其他免疫底盤。非同種異體反應(yīng)性的細(xì)胞毒性效應(yīng)細(xì)胞如NK細(xì)胞和γδT細(xì)胞，目前正在開發(fā)作為“現(xiàn)成的，貨架”工程化的基于細(xì)胞的產(chǎn)品[一個平臺139，140，141，142，143 ]。此外，還測試了在巨噬細(xì)胞和 B 細(xì)胞中表達(dá) CAR 的潛力，利用在抗原呈遞、吞噬作用和抗體產(chǎn)生中起作用的替代免疫細(xì)胞 [ 144 , 145 , 146 ]。

通過在適當(dāng)?shù)拿庖呒?xì)胞底盤中共表達(dá)某些基因，有可能破壞 TME 并提高基于細(xì)胞的療法對實(shí)體惡性腫瘤的整體療效。盡管已經(jīng)取得了巨大的進(jìn)步，但我們還沒有看到這些方法在臨床上是否有效，并且仍然存在許多實(shí)質(zhì)性障礙；特別是，當(dāng)前最先進(jìn)的工程載體和符合 GMP 的大規(guī)模生產(chǎn)用于過繼轉(zhuǎn)移的轉(zhuǎn)導(dǎo)細(xì)胞存在持續(xù)的技術(shù)和財(cái)務(wù)挑戰(zhàn)。更重要的是，與細(xì)胞因子釋放綜合征和靶向腫瘤外細(xì)胞毒性等副作用相關(guān)的罕見但危及生命的毒性構(gòu)成了潛在的安全問題。此外，CARs 和 BiTEs 等技術(shù)高度依賴于腫瘤抗原的表達(dá)，因此通常與實(shí)體瘤相關(guān)的抗原丟失現(xiàn)象可能會減弱。免疫選擇壓力后 MHC I 類表達(dá)的下調(diào)和抗原低/陰性惡性細(xì)胞的生長仍然是該領(lǐng)域和正在進(jìn)行的研究領(lǐng)域的重要限制。