HHS Vulnerability Disclosure, Help For data sharing requests, e-mail the corresponding author, Marion Subklewe (marion.subklewe@med.uni-muenchen.de). All the components of mouse mAbs, Overview of CAR-T cell therapy. Chemosphere. In the vast majority of patients, this is very minor and presents as blurred vision or dry, scratchy eyes. I imagine that in the future, patients are going to get 4 or 5 different drugs, some specific to enzyme pathways, others specific to their individual DNA sequencing. 10th ed. [The rates are] about 30% to 35% depending on which DREAMM study you look at. Tafasitamab (Monjuvi) is an antibody directed at the CD19 antigen, a protein on the surface of B lymphocytes. Unauthorized use of these marks is strictly prohibited. The CAR T-cell technology continues to improve. -, Martin FL, Martinez EZ, Stopper H, Garcia SB, Uyemura SA, Kannen V. Increased exposure to pesticides and colon cancer: Early evidence in Brazil. For patients who have multiple myeloma and adequate physiologic organ function, and agree to [undergo] transplant, transplant is considered standard. Serious side effects from this release can include: High fever and chills. The structure of different types of mAbs. We are going to be individualizing precision medicine and treating patients specific DNA abnormalities in their myeloma cells. Severe nausea, vomiting, and/or diarrhea. DREAMM-2 is the phase 2 trial that led to the FDA approval for the drug. Furthermore, T-cell subset composition and function determine the response to BiTE treatment.32,33 However, in the case of CAR T cells, T-cell composition and function at time of leukapheresis also influence CAR T function and are further modulated through patient- and disease-related parameters after transfusion. 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. In children and young adults with BCP-ALL with 3 months of follow-up, tisa-cel achieved a CR rate of 81%. These receptors can attach to proteins on the surface of lymphoma cells. T-cell transfer therapy. Besides common therapeutic approaches, such as surgery, chemotherapy, and radiotherapy, novel therapeutic approaches, including immunotherapy, have been an advent in CRC treatment. Several monoclonal antibodies are now used to treat non-Hodgkin lymphoma (NHL). Available Every Minute of Every Day. Common side effects can include nerve damage (neuropathy), low blood counts, fatigue, fever, nausea and vomiting, infections, diarrhea, and cough. The extent of BCMA positivity may be higher or lower for individual patients, but because they are all positive, BCMA serves as a very efficient target for BCMA-directed therapies. They [cause] very few bystander effects on other cells in the body. Whether you or someone you love has cancer, knowing what to expect can help you cope. The American Cancer Society is a qualified 501(c)(3) tax-exempt organization. In the lab, Dumbrava says, the T cells are modified to produce the CAR, which allows the T cells to attach to specific antigens on the tumor cells. Right now, belantamab mafodotin is being given as a single agent. We would give a triplet regimen, followed by transplant. Your doctor may check your blood for signs of an old hepatitis B infection before you start treatment. doi: 10.1016/j.chemosphere.2018.06.118. An example is blinatumomab (Blincyto), which binds to both CD19, a protein found on the surface of leukemia cells, and CD3, a protein on the surface of T cells. Abstract #577. The induction and consolidation therapies were 6-week cycles consisting of 4 weeks on and 2 weeks off, whereas the maintenance therapy was 4 weeks for every 12 weeks. All the components of human mAbs are derived from humans, Overview of CAR-T cell therapy. We didnt have that option when I started. With CAR T cells, patients get their therapy, get their response, and may not require treatment for an extended period of time. As well as personalized individual treatments using BiTEs or CAR T cells, one innovative way this could manifest itself is in the combination of BiTEs as an adapter strategy with universal CAR T cells that might overcome the clinical stings of T-cell dysfunction while maintaining the benefits of BiTE constructs. 27 Apr 2023 10:01:27 Common side effects can include numbness or tingling of hands/feet (peripheral neuropathy), low blood counts, fatigue, fever, decreased appetite, diarrhea, and pneumonia. On the other hand, T cell activation by genetically engineered CAR receptor via the TCR/CD3 and costimulatory domains can induce potent immune responses against specific tumor-associated antigens (TAAs). Ultimately, this will result in superior quality of life (QOL) for those patients who are going to get continuous therapy. Any sequence can be inserted into various portions of the antibody molecule. This drug can be used with bendamustine and rituximab to treat DLBCL, if the lymphoma has come back after receiving two other treatments. Schuster S., et al. Cancer Information, Answers, and Hope. There is a trial by the Multiple Myeloma Research Consortium that is using standard therapies and then doing next-generation sequencing to find out if there are specific gene mutations for which specific drugs can be directed toward. Studies evaluating these allogeneic. Chimeric antigen receptor (CAR)-modified T cells and BiTEs are both immunotherapies which redirect T cell specificity against a tumor-specific antigen through the use of antibody fragments. Clearly, challenges in production, manufacturing, and safety should be balanced against response rates. Unlike belantamab mafodotin, which, as we mentioned, needs to be combined with other agents to improve efficacy, CAR T-cell therapy alone has a response rate of 75% to 100%. In the ZUMA-1 trial, axi-cel treatment achieved an overall response rate (ORR) of 82%, including a 54% complete response (CR) with 1 year of follow-up, and 52% overall survival rate at 18 months in refractory large B-cell lymphoma. The generated CAR-T cells are cultivated and expanded in vitro. On the other hand, graft-versus-host disease and rejection of CAR T cells might counteract the benefit of allogeneic cell products.12, Comparison of blinatumomab vs CD19 CAR T cells. Other side effects can include low blood cell counts (with an increased risk of bleeding and serious infections), feeling tired or weak, loss of appetite, diarrhea, cough, fever, and swelling in the hands or legs. OncLive: What makes BCMA a logical target in multiple myeloma? official website and that any information you provide is encrypted Weve certainly made major headway, but their OS remains in the 4- to 6-year range, which is much lower than what we see with those patients who do not have adverse cytogenetic features. 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. Belantamab mafodotin-blmf (Blenrep) received regulatory approval in August 2020. These receptors can attach to proteins on the surface of lymphoma cells. Once its in the body, one part of the antibody attaches to the CD20 protein on B cells, while another part attaches to the CD3 protein on immune cells called T cells. Careers. Marion Subklewe; BiTEs better than CAR T cells. CAR-T- and a side order of IgG, to go?- Immunoglobulin . These drugs can cause severe birth defects if taken during pregnancy. Become a volunteer, make a tax-deductible donation, or participate in a fundraising event to help us save lives. The authors declare that they have no competing interests. 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 engineered CAR T . However, for reasons that we do not know, [belantamab mafodotin] can cause problems with the eye, [namely] keratopathy. Roschewski MJ, Wilson WH. CAR T-cell therapy Tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel) are the 2 CAR T-cell therapies currently approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to treat adult patients with relapsed/refractory (r/r) B-cell malignancies. Trouble breathing. It can also cause very low white blood cell counts, which increases the risk for serious infections. Cytokine release syndrome (CRS): As CAR T cells multiply, they can release large amounts of chemicals called cytokines into the blood, which can ramp up the immune system. The investigators are giving individual drugs, based on the patients DNA sequencing, that will attack specific abnormalities. Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma. It is a little bit confusing because, in theory, we could use [belantamab mafodotin] in the second- or third-line settings. This drug is infused into a vein (IV), typically every 3 weeks. This happens most often within the first day after the infusion, and it can be serious or even life-threatening. . PMC Tisa-cel achieved a 52% ORR, including a 40% CR rate, in adult patients with r/r DLBCL in the JULIET trial. Tisa-cel can also be used on a pediatric population and is indicated for patients <26 years with r/r B-cell precursor acute lymphoblastic leukemia (BCP-ALL).3 Currently, the only BiTE with FDA and EMA approval is blinatumomab, which redirects CD3+ T cells to CD19+ leukemic blasts. The great advantage of this approach is an increase in the safety profile, as the infusion can be stopped at any time, thereby reversing immune activation and immune-related adverse events. and transmitted securely. -, Thanikachalam K, Khan G. Colorectal cancer and nutrition. Chimeric antigen receptor (CAR)-T cell therapy has been revolutionary as it has produced remarkably effective and durable clinical responses 1. Pharmacological immunosuppression, such as using tocilizumab and/or corticosteroids, is necessary to manage these toxicities.13 In contrast, because of its short half-life, blinatumomab treatment can be interrupted or discontinued if necessary, without prolonged effect. The .gov means its official. Neelapu SS, Locke FL, Bartlett NL, et al. This is exciting for patients and their families. 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. Both of these approaches have beneficial anti-tumor effects on CRC. Your doctor will check your blood cell counts regularly during your treatment. Yet those productswhich include cell therapies, such as chimeric antigen receptor (CAR) T-cell therapy for aggressive B-cell lymphomas, and gene therapies to treat a range of monogenic rare diseaseshave proved transformative for patients. We keep striving for a cure. 2017;377(26):2531-2544. The clinical success of CAR T cell therapy for the treatment of B-ALL and diffuse large B cell lymphoma is due, in part, to targeting the CD19 antigen, an ideal candidate owing to its high . Therefore, since 2003, [multiple drugs have been] approved for the treatment of myeloma. It is not a BCMA-directed agent. The most advanced construct, the CD20 CD3 T-cellbispecific mosunetuzumab, has a rendered ORR of 37% in aggressive lymphoma with a CR rate of 19%.19 Several other clinical trials are currently recruiting patients for single or combinatorial approaches. They demonstrated remarkable efficacy in B cell hematologic malignancies, thus paving the way for their development in solid tumors. It can take 5-7 minutes to inject the drug, but this is much shorter than the time it normally takes to give the drug by vein. National Comprehensive Cancer Network (NCCN). Tumor flare: This drug might cause your tumor to grow or cause more symptoms for a time, which is known as tumor flare. Similar to the DREAMM studies, these agents are being combined with many of the standard therapies that we currently use. As a single agent, belantamab mafodotin is currently approved for patients who have been heavily pretreated with 4 or more prior lines of therapywhich is a lot of chemotherapy. In the JULIET trial, the median time from enrollment to infusion with tisa-cel was 54 days, and only 111 of 165 enrolled patients received cells.6 Seven percent of patients did not receive the treatment because of manufacturing failure, and an unreported number of patients were ineligible for inclusion in the trial due to low circulating lymphocyte counts. Other side effects can depend on which drug is given. CARs are engineered synthetic receptors that. 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. Cancer cells sometimes take advantage of these checkpoints to avoid being attacked by the immune system. 2018;68:394424. Early intervention using tocilizumab was shown to reduce the frequency of severe CRS in multiple . The increasing use of multiple immunomodulatory (IMD) agents for cancer therapies (e.g. 2019;16:235245. Serious infections: Some people might get a serious infection while getting this drug. This drug can cause some of the same side effects as other antibodies that target CD20, including infusion reactions (see above). Iran J Immunol. More serious reactions can include chest pain, heart racing, swelling of the face and tongue, cough, trouble breathing, feeling dizzy or lightheaded, and feeling faint. These [agents] had significantly fewer bystander effects on normal cells. This work was supported by German Research Council provided within the Sonderforschungsbereich SFB 1243, the Bavarian Elite Graduate Training Network, and the Wilhelm Sander Stiftung (project number 2018.087.1). Abeloffs Clinical Oncology. This approach enables escalation of the titrated BiTE dose while maintaining a favorable safety profile. Two companies are neck-and-neck with the FDA submission for CAR T-cell therapy approval. This is in sharp contrast to blinatumomab treatment in which responding patients often recover their neutrophil counts while receiving blinatumomab infusion, resulting into a lower rate of short-term infectious complications.4 After either blinatumomab or CD19 CAR T-cell infusion, long-term B-cell aplasia and hypogammaglobulinemia have been reported, although it is more profound after CAR T-cell therapy. 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. CEA plasmid as therapeutic DNA vaccination against colorectal cancer. How has the DREAMM series evolved since the approval? CAR T-cell therapy can cause a serious side effect known as cytokine release syndrome. 2018. Over the course of the past few years, we found that giving combination therapies with multiple mechanisms of action results in superior activity, such that triplets appear to be the standard of care for newly diagnosed patients. Age was a particularly variant factor between study cohorts. The DREAMM series is an ongoing effort to improve the outcome of single-agent belantamab mafodotin. The drug does not [elicit] an overly robust response rate as a single agent. Freedman AS, Jacobson CA, Mauch P, Aster JC. National Comprehensive Cancer Network (NCCN). Here you'll find in-depth information on specific cancer types including risk factors, early detection, diagnosis, and treatment options. The antibody acts like a homing signal, bringing the chemo drug to lymphoma cells, where it enters the cells and kills them. However, the BiTE platform offers a higher flexibility for combinatorial and sequential approaches from a toolbox of targeting and immunomodulatory antibody constructs. Version 3.2018. The fourth-generation CAR-T cells, based on the second-generation CARs, can induce cytokine production. Chapter 103: Non-Hodgkins lymphoma. The FDA approval of belantamab mafodotin was based on data from the DREAMM-2 trial. DeVita, Hellman, and Rosenbergs Cancer: Principles and Practice of Oncology. In the ELIANA trial, 75 of 92 enrolled patients received tisa-cel, with a median of 45 days from enrollment to infusion. of cycles: 1-2; in-hospital days: r/r setting: 9 d within the first cycle (MRD setting: 3 d), 2 d second cycle; additional costs: pump equipment, possible IgG-replacement therapy for 6-12 mo, Products: > US$350000; no. sharing sensitive information, make sure youre on a federal Allogeneic CAR T-cell therapy opens [the option] up for those patients, as well as for the patients who need treatment sooner rather than later; some patients cannot wait 2 to 4 weeks for the cells to be generated. This is done by replacing part of the antibody polypeptide with a fragment of a microbial antigen. From a hematologic standpoint, it can lower white [blood cell] counts and platelet counts, but that is usually not a major consequence. Monoclonal antibodies (mAbs) and chimeric antigen receptor (CAR) T cells are two branches of cancer immunotherapy. 2019;11:164. doi: 10.3390/nu11010164. CAR T-cell therapy is an exciting area now. In this regard, BiTEs compare favorably to CAR T cells once the costs of production, logistics, treatment, days of hospitalization, and short- and long-term adverse events have been considered (Table 1).37 Importantly, the long-term response rate to BiTEs and CAR T-cell therapy is critical to estimate the cost-effectiveness of these novel treatment platforms. It can also cause some other, more serious side effects, including: Cytokine release syndrome (CRS): This side effect can occur when T cells in the body release chemicals (cytokines) that ramp up the immune system. Then we come back with salvage therapy, usually with triplet regimens, of which there are a number approved by the FDA for patients who have had 1 to 3 prior lines of therapy. Some people have infusion reactions while getting this drug, which can cause symptoms like chills, flushing, headache, or shortness of breath during the infusion. Accessed at https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf on May 2, 2018. Tell your health care team right away if you have a fever, cough, chest pain, shortness of breath, sore throat, rash, or pain when urinating. Moreover, it is expensive and time consuming. 2010;11:753762. This opens up a wide avenue of patients with multiple myeloma who may have exhausted all other potential treatments. To me, this is the most exciting area because it is a one-and-done [approach] versus continued therapy. In this case, the antibody directed against CD19 acts like a homing signal by attaching to the CD19 protein on cancer cells, bringing the chemo directly to them. Immunotherapy is treatment that either boosts the patients own immune system or uses man-made versions of the normal parts of the immune system to kill lymphoma cells or slow their growth. Could you describe the unique safety profile of belantamab mafodotin? National Library of Medicine In the r/r setting, antigen loss and other adaptive immune escape strategies counteract the initial higher response rate of CD19 CAR T cells. Clipboard, Search History, and several other advanced features are temporarily unavailable. Because of these kinds of reactions, drugs to help preventthem aregiven before each infusion. Seven cases had product-related issues.7 However, in the pivotal ZUMA-1 trial, the manufacture of axi-cel failed for only 1 of 111 patients. It is approved for use in patients with follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia. Search for other works by this author on: Bispecific antibodies [published correction appears in, T cell-engaging therapies - BiTEs and beyond, Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia, Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia [published correction appears in, Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma, Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia, Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma, Reducing ex vivo culture improves the antileukemic activity of chimeric antigen receptor (CAR) T cells, A novel method to generate T-cell receptor-deficient chimeric antigen receptor T cells, Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. Cytokines are immune substances that have many different functions in the body. How does this agent compare with others in the space? However, looking at grade 3 CRS and ICANS in blinatumomab-treated patients, the event rate was much lower compared with the CAR T trials, with 4.9% for CRS and 9% for ICANS. Further, CAR T-cell therapy is [a] one-and-done [approach]. Although they share a common antigen target in the B-cell lineage surface protein CD19, they differ in their intracellular costimulatory domain (4-1BB vs CD28). Because CAR T-cell therapy can have serious side effects, it is only given in medical centers that have special training with this treatment. It is an ADC where the antibody is directed against BCMA and is conjugated to a chemotherapy drug. This article has a companion Point by Molina and Shah. Philadelphia, Pa: Lippincott Williams & Wilkins; 2015. 5th ed. The aim of checkpoint inhibitors is to release the brakes that block the action of the immune system against the tumor. 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. 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 immunotherapy approaches try to elicit patients` immune responses against tumor cells to eradicate the tumor. Ive been caring for patients with multiple myeloma for over 30 years, and treatments have evolved tremendously over the years. -. Looking ahead, we need predictive biomarkers to stratify patients to the treatment option with the highest likelihood of cure and mitigate clinical and financial toxicity. Brexucabtagene autoleucel (Tecartus, also known as brexu-cel) is approved to treat adults with mantle cell lymphoma that has come back or is no longer responding to other treatments. Finally, both treatment platforms are associated with high financial toxicity. Emerging data indicate that [quadruplets] are even more efficacious without a significant increase in toxicity. In the context of CAR T cells, in vitro studies have demonstrated the reversal of T-cell exhaustion through drug-induced regulation. 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. Selinexor is an [oral] pill given once or twice a week, depending on the schedule. How do you approach sequencing in your own practice? In this review, we outline the mechanisms of action (MOA) of approved, antibody-based IMD agents, potentially related . Hill JA, Giralt S, Torgerson TR, et al. N Engl J Med. IgE antibodies targeting cancer antigens can be used for immunotherapy. Over recent years, bispecific antibodies have been engineered in >50 different formats, including dual-affinity retargeting proteins, tandem diabodies, and bi-nanobodies, but in oncology, the bispecific T-cell engagers (BiTEs) are the most developed and thus are the focus of this article.1 Both BiTE and CAR approaches are independent of the specificity of the endogenous T-cell receptor and independent of major histocompatibility complex on tumor cells. Tell your health care team if you notice tender or swollen lymph nodes, chest pain, cough, trouble breathing, or pain or swelling around a known tumor. For reprint requests, please see our Content Usage Policy. Practice Guidelines in Oncology: T-cell Lymphomas. These drugs can also increase your risk of certain serious infections for many months after the drug is stopped. Although quadruplets are quite effective up front, they are not FDA approved at this point in time. The biggest hurdle that we still have in multiple myeloma is [treating] patients with high-risk disease based on [their] cytogenetics and staging. Cancer.org is provided courtesy of the Leo and Gloria Rosen family. Most of the [newer treatments] are more sensitive and specific to myeloma cells with much less bystander effect. Ask your doctor what you can expect. Whether you want to learn about treatment options, get advice on coping with side effects, or have questions about health insurance, were here to help. Belantamab mafodotin was approved in kind of a niche sense in that it is approved for patients who had 4 prior lines of therapy. The time sequence of the reversibility depends on how severe [the toxicity] is. Although this occurs in about 80% of patients treated with the drug, severe reactions occur in about 10% of patients. Thus, the overall safety profile appears to be better for BiTE molecules than for CAR T cells. 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.