Because CAR T-cell therapy can have serious side effects, it is only given in medical centers that have special training with this treatment. Axicabtagene ciloleucel (Yescarta, also known as axi-cel) is a type of CAR T-cell therapy approved to treat people with: Tisagenlecleucel (Kymriah, also known as tisa-cel) is approved to treat people with diffuse large B-cell lymphoma, high grade B-cell lymphoma, and diffuse large B-cell lymphoma arising from follicular lymphoma, as well as follicular lymphoma that hasnt responded to or has come back after other therapies,after trying at least two other kinds of treatment. David H. Vesole, MD, PhD, discusses the evolution of multiple myeloma treatment, and explained how other BCMA-therapies are poised to impact clinical practice. In patients with r/r BCP-ALL, blinatumomab treatment achieved a 44% CR rate with full, partial, or incomplete hematologic recovery, as compared with the 25% achieved by chemotherapy. Most reactions are mild, such as itching, chills, fever, nausea, rashes, fatigue, and headaches. CAR T-cell therapy is likely going to be approved sometime in the first quarter of 2021. Become a volunteer, make a tax-deductible donation, or participate in a fundraising event to help us save lives. Man-made versions, called monoclonal antibodies, can be designed to attack a specific target, such as a substance on the surface of lymphocytes (the cells in which lymphomas start). B cells are a type of white blood cell. government site. Physician Data Query (PDQ). We're improving the lives of cancer patients and their families through advocacy, research, and patient support to ensure that everyone has an opportunity to prevent, detect, treat, and survive cancer. Considering the high rate of antigen loss, multitargeting adapter CAR T and dual-targeting CAR T cells appear a promising tool for combinatorial and/or sequential approaches. The data strongly support the use of blinatumomab in MRD-positive patients with BCP-ALL. Currently, triplet therapy seems to be the standard of care, but what is evolving is whether we should give quadruplet regimens with monoclonal antibodies in addition to those same 3 classes of drugs I mentioned. The T cells are then multiplied in the lab and given back into the patients blood, where they can seek out the lymphoma cells and launch a precise immune attack against them. A study comparing JNJ-68284528, a CAR-T therapy directed against B-cell maturation antigen (BCMA), versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and . Yes, we could have a BCMA-directed target, but if we add that with a targeted agent against some specific enzyme deficiency or genetic abnormality, it [will be a valuable] addition to these other mechanisms. The median time from leukapheresis to delivery was 17 days, and 101 of these patients received treatment.8 The long turnaround times are clinically relevant, as patients carry a high intrinsic risk for disease progression during the production process. Neelapu SS, Locke FL, Bartlett NL, et al. This drug can be used along with lenalidomide (see Immunomodulating drugs, below) to treat diffuse large B-cell lymphoma (DLBCL) that has come back or is no longer responding to other treatments, in people who cant have a stem cell transplant for some reason. This is exciting for patients and their families. These treatments can also sometimes cause serious, Other serious side effects of these treatments can include. Clinical trials related to TCR-T cell therapy and monoclonal antibodies designed for overcoming immunosuppression, and recent advances made in understanding how TCRs are additionally examined. OncLive: What makes BCMA a logical target in multiple myeloma? conceived and wrote the manuscript. In addition to easier access, third-party cell donors might help to overcome the issues of lymphopenia and disease- and patient-related T-cell dysfunction that compromise the success of adoptively transferred autologous cell products. BCMA-directed therapies, such as bispecific monoclonal antibodies, CAR T-cell therapy, and antibody-drug conjugates (ADCs), are in the midst of transforming the treatment paradigm of relapsed/refractory multiple myeloma to get closer to a cure for patients, said David H. Vesole, MD, PhD. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds. Federal government websites often end in .gov or .mil. CARs are fusion proteins of a selected single-chain fragment variable from a specific monoclonal antibody . 5th ed. Although the production process is well established, it is only feasible in patients with sufficient peripheral counts, and each treatment involves several steps, each of which carries the possibility of error. Finally, CAR-T cells are infused into the patients bloodstream to kill the tumor cells, Five generations of CAR-T cells. Pan et al27 demonstrated in a small pediatric BCP-ALL population the feasibility of sequentially administering CD19 CAR T cells followed by CD22 CAR T cells. Additionally, DREAMM-12 and DREAMM-13 are evaluating belantamab mafodotin in patients with renal failure and liver abnormalities, [respectively]. Polatuzumab vedotin (Polivy) is an anti-CD79b antibody attached to a chemotherapy drug (an antibody-drug conjugate). 2019;16:235245. Common side effects can include numbness or tingling of hands/feet (peripheral neuropathy), low blood counts, fatigue, fever, decreased appetite, diarrhea, and pneumonia. Would you like email updates of new search results? We can also help you find other free or low-cost resources available. How do you see CAR T-cell therapy impacting the landscape of multiple myeloma? 8600 Rockville Pike The increasing interval of BiTE application during maintenance therapy (induction, 2 weeks; maintenance, 8-week treatment-free interval) is most likely sufficient to reverse an exhausted T-cell state. Practice Guidelines in Oncology: T-cell Lymphomas. Leaked Data Show Cilta-cel Delivers 74% Reduction in Risk of Progression in Early Relapsed/Refractory Myeloma, Jakubowiak Highlights PFS Benefit Seen With KRd Maintenance in Newly Diagnosed Multiple Myeloma, FDA Accepts sBLA for Ide-cel in Triple-class Exposed Relapsed/Refractory Myeloma, FDA Approval Insights: Pirtobrutinib in MCL, Retrospective Study Provides Real-World Insight on Ide-cel in R/R Multiple Myeloma With Renal Impairment, FDA Places Partial Clinical Hold on Phase 1 Trial of MT-0169 in R/R Myeloma or Non-Hodgkin Lymphoma, Dr Daneschmand on Data From SunRISe-1 With TAR-200 and Cetrelimab in BCG-Unresponsive NMIBC, Dr Saad on PSA Response and Time to PSA Progression With Abiraterone Acetate and Olaparib in mCRPC, Pembrolizumab Monotherapy Demonstrates Clinical Efficacy in High-risk NMIBC, TAR-200 Produces High CR Rates, Tolerability in BCG-unresponsive NMIBC, OncLive National Fellows Forum: Lung Cancer 2023, Join us in Chicago for Giants of Cancer Care, Belantamab Mafodotin in Relapsed/Refractory Myeloma Requires Multidisciplinary Effort, Monoclonal Antibodies, ADCs, and CAR T Cells Invigorate the Myeloma Paradigm, From the Ophthalmologists Eye: Managing Ocular Toxicities With Belantamab Mafodotin in Myeloma, BCMA-Targeted Approaches Revolutionize Relapsed/Refractory Myeloma Treatment, Novel Combos With Belantamab Mafodotin May Move the Needle in Myeloma, | Join us in Chicago for Giants of Cancer Care. Accessed at https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf on May 2, 2018. Other novel formats, such as the multifunctional antibody construct that targets a tumor-associated antigen with high affinity and blocks an inhibitory checkpoint molecule with low affinity, will be tested.29 Alternative constructs elicit a combination of simultaneous blockade of immune checkpoint molecules and costimulation30 or provide targeting and stimulating within one construct.31 Also, the CAR T-cell platform enables different strategies to be used to block the inhibitory PD-1 signal, including CRISPR-Cas9mediated PD-1 disruption. . 2017;377(26):2531-2544. Harnessing the power of immune cells, especially T cells, to enhance anti-tumor activities has become a promising strategy in clinical management of hematologic malignancies. T cells are removed from a patient through a process like a blood draw. Weve invested more than $5 billion in cancer research since 1946, all to find more and better treatments, uncover factors that may cause cancer, and improve cancer patients quality of life. An antibody-drug conjugate (ADC) is a monoclonal antibody linked to a chemotherapy drug. Although [these agents] are not completely devoid of other toxicities, they focus predominantly on myeloma cells. Toxicity and management in CAR T-cell therapy, Comparing CAR T-cell toxicity grading systems: application of the ASTCT grading system and implications for management, How I prevent infections in patients receiving CD19-targeted chimeric antigen receptor T cells for B-cell malignancies, Tumor regression in cancer patients by very low doses of a T cell-engaging antibody, Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma, Open-label, phase 2 study of blinatumomab as second salvage therapy in adults with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma [abstract], Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor therapies and is active in treatment through multiple lines [abstract], Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL, Blinatumomab vs historic standard-of-care treatment for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukaemia, Long-term follow-up of CD19 CAR therapy in ALL, Tumor antigen escape from CAR T cell therapy, Catch me if you can: leukemia escape after CD19-directed T cell immunotherapies, Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia, Mechanisms of resistance to CAR T cell therapy, Sequential CD19-22 CAR T therapy induces sustained remission in children with r/r B-ALL, PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR, Bifunctional PD-1 CD3 CD33 fusion protein reverses adaptive immune escape in acute myeloid leukemia, Agonist redirected checkpoint, PD1-Fc-OX40L, for cancer immunotherapy, BCMA-targeting bispecific antibody that simultaneously stimulates NKG2D-enhanced efficacy against multiple myeloma, Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody blinatumomab in patients with B-precursor ALL, Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment, Pharmacologic control of CAR-T cell function using dasatinib, Emerging approaches for regulation and control of CAR T cells: a mini review, Value and affordability of CAR T-cell therapy in the United States, Clinical lessons learned from the first leg of the CAR T cell journey, The response to lymphodepletion impacts PFS in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells, Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell, Long-term follow-up of serum immunoglobulin levels in blinatumomab-treated patients with MRD-positive BCP-ALL, Outcome of patients with relapsed/refractory ALL after blinatumomab failure: No change in the level of CD19 expression, T-cell responses against CD19+ pediatric acute lymphoblastic leukemia mediated by bispecific T-cell engager (BiTE) are regulated contrarily by PD-L1 and CD80/CD86 on leukemic blasts, c-Jun overexpression in CAR T cells induces exhaustion resistance, 2021 by The American Society of Hematology, Copyright 2023 by American Society of Hematology, BiTE vs CAR T-cell availability: off the shelf vs individualized good manufacturing practices production, https://doi.org/10.1182/bloodadvances.2020001792, Blinatumomab: pediatric and adult patients with r/r ALL, MRD, Axi-cel: adult with r/r (>2 prior Tx lines) DLBCL, PMBCL, Tisa-cel: r/r ALL <26 y of age, adults with r/r (>2 prior Tx lines) DLBCL, Blinatumomab: pediatric (>1 y of age) r/r ALL and adults with r/r Ph, Axi-cel: adults with r/r (>2 prior Tx lines) DLBCL, PMBCL, Tisa-cel: r/r ALL <26 y of age; adults with r/r (>2 prior Tx lines) DLBCL, Retro- or lentiviral-transduced CAR T cells, 17-54 d from patient presentation to CAR T transfusion (national vs international patient recruitment, different trial design), CAR T-cell product variability due to differences in T-cell subset composition, CAR transduction efficacy, number of viable CAR T cells; number of transfused CAR T cells differs from 0.2 10, Engineered, commonly using autologous CD4 and CD8 T cells, Relies on endogenous T-cell composition and function at time of infusion, Relies on T-cell composition and function at time of leukapheresis; further modulation of CAR T function after transfusion through patient- and disease-related parameters (eg TME), Lymphodepletion prior to start of therapy, Lymphodepletion with cyclophosphamide and fludarabine prior to CAR T-cell transfusion mandatory (tisa-cel: exceptions in case of WBCs <110, CRS:4.9%, ICANS: 9%, hematotoxicity: neutropenia: 28%; lymphopenia: 1.5%; decrease in white-cell count: 5.2%; decrease in platelet count: 6.4% (lower rate of infections compared with SOC; short half-life (<2 h), interruption possible, CRS: 46%; ICANS: 12%-32%; hematotoxicity: 23%-45%; JULIET trial: cytopenia not resolved by day 28: 32%, CAR T cells persist for months/years, Neoplasia through genetic interference, genotoxic side effects, Recovery after completion of infusion: 6-18 mo, Months to years depending on persistence of functional CAR T cells; hypogammaglobulinemia for months to years, Product: US$72000; average no. The drug does not [elicit] an overly robust response rate as a single agent. Biologically, the monoclonal antibody attaches to the myeloma cell, which is endocytosed into the cell. The site is secure. The generated CAR-T cells are cultivated and expanded in vitro. In the TOWER trial of blinatumomab, patients received 2 cycles of induction therapy followed by up to 3 cycles of consolidation therapy if necessary and then 12 months of maintenance therapy. The most common side effects are fever, chills, nausea, and rashes. [Moreover,] there is at most a 10-day window in which these. A 54% (7/13) ORR (including 5 CRs and 2 PRs) . CAR T-cell therapy can cause toxicities, but in contrast to lymphoma and leukemia, most of them are minor in multiple myeloma. This article has a companion Point by Molina and Shah. Tisa-cel, axi-cel, and blinatumomab all target CD19, and loss of this surface marker plays a key role in the development of resistance to these treatments.23 Notably, the incidence of CD19 loss was lower in patients receiving blinatumomab (12% to 21% in ALL) compared with tisa-cel and axi-cel (9% to 25% in ALL and 27% to 35% in DLBCL).24-26 A potential explanation for this clinical observation might be the difference in dosing schedule, that is, intermittent vs continuous exposure to CD19-directed immunotherapy. It wasnt until proteasome inhibitors (PIs), which were enzyme-specific pathway inhibitors that were first approved in 2003, that we started [using] targeted therapies for specific pathways and cells. doi: 10.1016/j.chemosphere.2018.06.118. receives industry research support from Amgen, Gilead, Miltenyi, Morphosys, Roche, and Seattle Genetics; is on the advisory boards of Amgen, Celgene, Gilead, Janssen, Novartis, Pfizer, BMS, and Seattle Genetics; and is on the speakers bureau at Amgen, Celgene, Gilead, Janssen, Novartis, and Pfizer.