Recent updates on CAR T clinical trials for multiple myeloma

Lin, Quande; Zhao, Juanjuan; Song, Yongping; Liu, Delong

doi:10.1186/s12943-019-1092-1

Cited by 81 publications

(75 citation statements)

References 115 publications

(85 reference statements)

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“…In this context, a plausible option is to maximize the killing capacity of bispecific antibodies, death receptor antibodies and CAR T-cells by increasing their affinity to MM-cells. Another option could be to improve the overall avidity of T-cells toward MM-cells by endowing them with dual or multiple CARs, whereby more than one single MM-associated antigen can be targeted [99]. Improving the interaction between T-cells and MM-cells this way can also result in more efficient lysis levels, which is required to overcome the BM-ME-mediated resistance.…”

Section: Discussionmentioning

confidence: 99%

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Holthof

Mutis

2020

Cancers

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The power of immunotherapy in the battle of Multiple Myeloma (MM) started with allogeneic stem cell transplantation, and was rediscovered with immunomodulatory drugs and extended with the outstanding results achieved with targeted antibodies. Today, next to powerful antibodies Elotuzumab and Daratumumab, several T-cell-based immunotherapeutic approaches, such as bispecific antibodies and chimeric antigen receptor-transduced T-cells (CAR T-cells) are making their successful entry in the immunotherapy arena with highly promising results in clinical trials. Nonetheless, similar to what is observed in chemotherapy, MM appears capable to escape from immunotherapy, especially through tight interactions with the cells of the bone marrow microenvironment (BM-ME). This review will outline our current understanding on how BM-ME protects MM-cells from immunotherapy through immunosuppression and through induction of intrinsic resistance against cytotoxic effector mechanisms of T- and NK-cells.

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Section: Discussionmentioning

confidence: 99%

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Holthof

Mutis

2020

Cancers

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“…CAR-T therapy targets for multiple myeloma include BCMA, CD19, SLAMF7 (CS1), NKG2D, CD56, CD70, CD38, CD138, CD44v6, and IgκλC. Among them, BCMA is the most studied [69,70]. Two BCMAtargeted CAR-T clinical trials (bb2121 and LCAR-B38M) evidenced a 50-74% CR rate, a 10.8-16-month duration of response, and an 11.8-15-month PFS [71,72].…”

Section: Fast and Furious Development Of Cell Therapymentioning

confidence: 99%

Next-generation immuno-oncology agents: current momentum shifts in cancer immunotherapy

et al. 2020

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Cancer immunotherapy has reached a critical point, now that immune checkpoint inhibitors and two CART products have received market approval in treating 16 types of cancers and 1 tissue-agnostic cancer indication. Accompanying these advances, the 2018 Nobel Prize was awarded for the discovery of immune checkpoint pathways, which has led to the revolution of anti-cancer treatments. However, expanding the indications of immuno-oncology agents and overcoming treatment resistance face mounting challenges. Although combination immunotherapy is an obvious strategy to pursue, the fact that there have been more failures than successes in this effort has served as a wake-up call, placing emphasis on the importance of building a solid scientific foundation for the development of next-generation immuno-oncology (IO) agents. The 2019 China Cancer Immunotherapy Workshop was held to discuss the current challenges and opportunities in IO. At this conference, emerging concepts and strategies for IO development were proposed, focusing squarely on correcting the immunological defects in the tumor microenvironment. New targets such as Siglec-15 and new directions including neoantigens, cancer vaccines, oncolytic viruses, and cytokines were reviewed. Emerging immunotherapies were discussed in the areas of overcoming primary and secondary resistance to existing immune checkpoint inhibitors, activating effector cells, and targeting immunosuppressive mechanisms in the tumor microenvironment. In this article, we highlight old and new waves of IO therapy development, and provide perspectives on the latest momentum shifts in cancer immunotherapy.

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“…In the first early clinical trial using a BCMA-targeted CAR design, among the 12 patients in the trial, three patients entered partial remission, three patients had a stable disease and one patient achieved complete remission (NCT02215967). Further developments of the CAR design, still targeting BCMA but with the addition of the 4-1BB costimulatory domain, which is shown to increase T cell persistence, were then trialled and showed that clinical response was dose dependent and a 100% complete response was recorded with the higher dose of 450 × 10 6 CAR T cells [17]. Several CAR constructs targeting BCMA are in clinical trial, with the hope that soon they will be approved for clinical therapy, improving the outcome for MM patients.…”

Section: Haematological Cancersmentioning

confidence: 99%

Advances in Anti-Cancer Immunotherapy: Car-T Cell, Checkpoint Inhibitors, Dendritic Cell Vaccines, and Oncolytic Viruses, and Emerging Cellular and Molecular Targets

Alard

Butnariu

Grillo

et al. 2020

Cancers

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Unlike traditional cancer therapies, such as surgery, radiation and chemotherapy that are typically non-specific, cancer immunotherapy harnesses the high specificity of a patient’s own immune system to selectively kill cancer cells. The immune system is the body’s main cancer surveillance system, but cancers may evade destruction thanks to various immune-suppressing mechanisms. We therefore need to deploy various immunotherapy-based strategies to help bolster the anti-tumour immune responses. These include engineering T cells to express chimeric antigen receptors (CARs) to specifically recognise tumour neoantigens, inactivating immune checkpoints, oncolytic viruses and dendritic cell (DC) vaccines, which have all shown clinical benefit in certain cancers. However, treatment efficacy remains poor due to drug-induced adverse events and immunosuppressive tendencies of the tumour microenvironment. Recent preclinical studies have unveiled novel therapies such as anti-cathepsin antibodies, galectin-1 blockade and anti-OX40 agonistic antibodies, which may be utilised as adjuvant therapies to modulate the tumour microenvironment and permit more ferocious anti-tumour immune response.

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Recent updates on CAR T clinical trials for multiple myeloma

Cited by 81 publications

References 115 publications

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Next-generation immuno-oncology agents: current momentum shifts in cancer immunotherapy

Advances in Anti-Cancer Immunotherapy: Car-T Cell, Checkpoint Inhibitors, Dendritic Cell Vaccines, and Oncolytic Viruses, and Emerging Cellular and Molecular Targets

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