Clinical Updates Regarding Multiple Myeloma From the 2019 American Society of Hematology Annual Meeting

In this review, we summarize novel clinical data on multiple myeloma (MM) that were presented at the 2019 annual meeting of the American Society of Hematology. The Master trial showed that a response-adapted approach may effectively guide therapeutic decisions in terms of treatment intensification after autologous transplantation among patients with newly diagnosed MM. The Alcyone study confirmed the superiority of adding daratumumab to the backbone combination of bortezomib, melphalan, and dexamethasone among diagnosed MM patients unfit for transplantation, which resulted in a significant overall survival benefit. The Candor trial showed that the addition of daratumumab to carfilzomib and dexamethasone is associated with a significant benefit in progression-free survival among patients with relapsed/refractory MM after 1 to 3 prior lines of therapy. Novel agents including selinexor- and venetoclax-based combinations offer new therapeutic choices for relapsed/refractory MM. Furthermore, the trispecific CC-93269 represents the new generation of highly active T-cell engagers. Chimeric antigen receptor T-cell constructs show significant efficacy among patients with heavily pretreated relapsed/refractory MM; however, the sustainability of responses remains a challenge.     

CAR-T细胞免疫治疗相关的不良反应研究进展

CAR-T细胞治疗血液系统恶性肿瘤疗效显著,但是,同时观察到不良反应的发生,常见的非血液学不良反应有:细胞因子释放综合征、CAR-T治疗相关脑病综合征,血液学不良反应有:噬血细胞淋巴组织细胞增多症、弥散性血管内凝血、B细胞发育不良、造血功能恢复延迟。这些不良反应经积极治疗,多数可得到纠正,但是仍有部分不良反应加重后危及患者生命,如果能早期识别、对高危患者采取预防措施,避免严重不良反应的发生,那么该疗法就能使更多的患者获益。为此,本文就上述不良反应的临床特征、病理生理机制、处理措施及高风险患者的评估和预测作一综述。     

Chimeric antigen receptor T cells (CAR-T) for the treatment of T-cell malignancies

At present, the only curative therapy for patients with T-cell malignancies is allogeneic stem cell transplant, which has associated risks and toxicities. Novel agents have been tried in relapsed T-cell acute lymphoblastic leukemia (T-ALL), but only one, with 20%–30% complete remission rates, has been approved by the US Food and Drug Administration. T-ALL is a heterogeneous disease, but it has universal overexpression of CD7 as well as several other T-cell markers, such as CD2 and CD5. T cells engineered to express a chimeric antigen receptor (CAR) are a promising cancer immunotherapy. Such targeted therapies have shown great potential for inducing both remissions and even long-term relapse-free survival in patients with B-cell leukemia and lymphoma. UCART7 for CD7⁺ T-cell malignancies is in development for treatment of relapsed T-ALL in children and adults. It may also have potential in other CD7⁺ hematologic malignancies that lack both effective therapies and targeted therapies. The challenges encountered and progress made in developing a novel fratricide-resistant “off-the-shelf” CAR-T (or UCART7) that targets CD7⁺ T-cell malignancies are discussed here.     

CAR-T细胞治疗实体瘤的挑战与应对策略

嵌合抗原受体T细胞（CAR-T）作为肿瘤免疫治疗的新疗法,已在多种血液肿瘤的临床治疗中取得了突破性进展,但用于实体瘤的治疗仍面临着诸多挑战。本文根据CAR-T细胞在实体瘤中的应用情况,总结其疗效不佳的原因,包括缺乏肿瘤特异性靶抗原、T细胞的转运及肿瘤浸润障碍、肿瘤微环境的免疫抑制等;并以此分析可行的解决策略,如提高肿瘤细胞特异性、提高对实体瘤的转运及浸润、解除免疫抑制以及提高CAR-T细胞在体内的持久性等,以期为后续CAR-T细胞治疗实体肿瘤研究提供思路。     

Immunotherapy-Related Acute Kidney Injury

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Novel TCR-based biologics: mobilising T cells to warm ‘cold’ tumours

Immunotherapeutic strategies have revolutionised cancer therapy in recent years, bringing meaningful improvements in outcomes for patients with previously intractable conditions. These successes have, however, been largely limited to certain types of liquid tumours and a small subset of solid tumours that are known to be particularly immunogenic. Broadening these advances across the majority of tumour indications, which are characterised by an immune-excluded, immune-deserted or immune-suppressed (‘cold’) phenotype, will require alternative approaches that are able to specifically address this unique biological environment. Several newer therapeutic modalities, including adoptive cell therapy and T cell redirecting bispecific molecules, are considered to hold particular promise and are being investigated in early phase clinical trials across various solid tumour indications. ImmTAC molecules are a novel class of T cell redirecting bispecific biologics that exploit TCR-based targeting of tumour cells; providing potent and highly specific access to the vast landscape of intracellular targets. The first of these reagents to reach the clinic, tebentafusp (IMCgp100), has generated demonstrable clinical efficacy in an immunologically cold solid tumour with a high unmet need. Here, we highlight the key elements of the ImmTAC platform that make it ideally positioned to overcome the cold tumour microenvironment in an off-the-shelf format.     

Anti-cancer vaccine therapy for hematologic malignancies: An evolving era

The potential promise of therapeutic vaccination as effective therapy for hematologic malignancies is supported by the observation that allogeneic hematopoietic cell transplantation is curative for a subset of patients due to the graft-versus-tumor effect mediated by alloreactive lymphocytes. Tumor vaccines are being explored as a therapeutic strategy to re-educate host immunity to recognize and target malignant cells through the activation and expansion of effector cell populations. Via several mechanisms, tumor cells induce T cell dysfunction and senescence, amplifying and maintaining tumor cell immunosuppressive effects, resulting in failure of clinical trials of tumor vaccines and adoptive T cell therapies. The fundamental premise of successful vaccine design involves the introduction of tumor-associated antigens in the context of effective antigen presentation so that tolerance can be reversed and a productive response can be generated. With the increasing understanding of the role of both the tumor and tumor microenvironment in fostering immune tolerance, vaccine therapy is being explored in the context of immunomodulatory therapies. The most effective strategy may be to use combination therapies such as anti-cancer vaccines with checkpoint blockade to target critical aspects of this environment in an effort to prevent the re-establishment of tumor tolerance while limiting toxicity associated with autoimmunity.     

Immuno-oncologic Approaches: CAR-T Cells and Checkpoint Inhibitors

Advances in understanding myeloma biology have shown that disease progression is not only the consequence of intrinsic tumor changes but also of interactions between the tumor and the microenvironment in which the cancer grows. The immune system is an important component of the tumor microenvironment in myeloma, and acting on the immune system is an appealing new treatment strategy. There are 2 ways to act toward immune cells and boost antitumor immunity: (1) to increase antitumor activity (acting on T and NK cytotoxic cells), and (2) to reduce immunosuppression (acting on myeloid-derived stem cells and T regulatory cells). Checkpoint inhibitors and adoptive cell therapy (ACT) are 2 of the main actors, together with monoclonal antibodies and immunomodulatory agents, in the immune-oncologic approach. The aim of checkpoint inhibitors is to release the brakes that block the action of the immune system against the tumor. Anti-programmed death-1 (PD-1) and PD-1-Ligand, as well as anti-CTLA4 and KIR are currently under evaluation, as single agents or in combination, with the best results achieved so far with combination of anti–PD-1 and immunomodulatory agents. The aim of ACT is to create an immune effector specific against the tumor. Preliminary results on chimeric antigen receptor (CAR) T cells, first against CD19, and more recently against B-cell maturation antigen, have shown to induce durable responses in heavily pretreated patients. This review focuses on the most recent clinical results available on the use of checkpoint inhibitors and CAR-T cells in myeloma, in the context of the new immune-oncologic approach.