car t cell therapy vs monoclonal antibodies
The new monoclonal and bispecific antibodies and CAR-T, besides offering new perspectives in the overall survival and disease-free survival of patients, may also transform the epidemiology of infections in ALL by improving the toxicity of treatments. Targeting different tumor antigens, either simultaneously or sequentially, might be a strategy for bypassing this path of resistance. 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. Please enable it to take advantage of the complete set of features! There are 3 biological challenges that have led to failure in a portion of patients treated with anti-CD19 CAR T-cell therapy. Researchers are still studying this type of therapy and other ways of changing T cells to treat cancer. The drug does not [elicit] an overly robust response rate as a single agent. This type of treatment enhances the ability of your T cells to recognize and attack cancer cells. Overall survival (OS) [rates] have improved as well [compared with] when I first started more than 30 years ago. In children and young adults with BCP-ALL with 3 months of follow-up, tisa-cel achieved a CR rate of 81%. Further, CAR T-cell therapy is [a] one-and-done [approach]. Ive been caring for patients with multiple myeloma for over 30 years, and treatments have evolved tremendously over the years. Brentuximab can be used to treat some types of T-cell lymphoma, either as the first treatment (typically along with chemo) or if the lymphoma if it has come back after other treatments. The increasing use of multiple immunomodulatory (IMD) agents for cancer therapies (e.g. Accessed at https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq on May 3, 2018. Besides common therapeutic approaches, such as surgery, chemotherapy, and radiotherapy, novel therapeutic approaches, including immunotherapy, have been an advent in CRC treatment. These drugs can cause severe birth defects if taken during pregnancy. Serious side effects from this release can include: High fever and chills. Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer deaths worldwide. 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. There will likely be a lot of competing options for BCMA-directed therapy. 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. Practice Guidelines in Oncology: T-cell Lymphomas. And there are many more in development. 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. In the ELIANA trial, 75 of 92 enrolled patients received tisa-cel, with a median of 45 days from enrollment to infusion. The first is lack of initial expansion of collected lymphocytes in culture; the second, loss of CART T cells early in therapy; and the third, antigen escape. 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. The investigators are giving individual drugs, based on the patients DNA sequencing, that will attack specific abnormalities. Schuster S., et al. We are not going to control multiple myeloma with single agents. In: DeVita VT, Lawrence TS, Rosenberg SA, eds. Tafasitamab (Monjuvi) is an antibody directed at the CD19 antigen, a protein on the surface of B lymphocytes. Back in the day, all of our drugs were chemotherapies, which have a lot of bystander effects and can cause nausea and vomiting. 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). Tumor flare: This drug might cause your tumor to grow or cause more symptoms for a time, which is known as tumor flare. 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. Biologically, the monoclonal antibody attaches to the myeloma cell, which is endocytosed into the cell. 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. 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. 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. Dexamethasone was used in the TOWER trial prophylactically to prevent CRS and neurologic events; thus, blinatumomabs safety in this regard cannot be compared with tisa-cel or axi-cel. They demonstrated remarkable efficacy in B cell hematologic malignancies, thus paving the way for their development in solid tumors. Side effects of can include low white blood cell counts (with an increased risk of infection) and neuropathy (painful nerve damage), which can sometimes be severe and may not go away after treatment. 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. David H. Vesole, MD, PhD, discusses the evolution of multiple myeloma treatment, and explained how other BCMA-therapies are poised to impact clinical practice. and transmitted securely. Our group is a bit unique because we are not particularly in favor of maintenance therapy. It is approved for the treatment of r/r BCP-ALL, as well as BCP-ALL with minimal residual disease (MRD).4,5, Several aspects favor the application of bispecific T-cellrecruiting antibody constructs compared with the application of CAR T cells (Table 1). 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. 2018. 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. CAR T-cell therapy can cause toxicities, but in contrast to lymphoma and leukemia, most of them are minor in multiple myeloma. Conflict-of-interest disclosure: M.S. of treatment applications: 1; additional costs: logistics, leukapheresis, lymphodepleting chemotherapy, average 10-d in-hospital stay (outpatient to long-term stay, including ICU), possible IgG-replacement therapy for months to years, High flexibility to combine different BiTE constructs given in parallel or sequentially, dual-specific BiTE constructs in clinical trials, individualized combinatorial approach of targeting BiTE construct and immunomodulatory construct feasible, Various dual-targeting CAR T-cell constructs in clinical trials; possibility to apply simultaneously vs sequentially, Potentially, reversal through treatment-free intervals (induction: 4 wk on, 2 wk off; maintenance: 4 wk on, 8 wk off), Preclinical work: drug-induced cessation of CAR receptor signaling to prevent or reverse exhaustion; genetically engineered CAR T cells to counteract exhaustion. The CAR T-cell technology continues to improve. They show several advantages over monoclonal antibodies (Fig. Ultimately, this is what is going to happen. approved to treat people with diffuse large B, cell lymphoma arising from follicular lymphoma. 27 Apr 2023 10:01:27 Recently, in a pioneering first-in-human phase I . In contrast to CAR T cells, blinatumomab has an in vivo half-life of 2 to 4 hours and requires continuous IV infusion. They [cause] very few bystander effects on other cells in the body. However, most disease relapses do not feature loss of the target antigen but present with other immune-related escape mechanisms, including the upregulation of inhibitory checkpoint molecules, most commonly PD-L1.28 To reverse this adaptive immune escape mechanism, several antiPD-1 or antiPD-L1 monoclonal antibodies are currently used in combination with blinatumomab and CAR T cells. What does it take to outsmart cancer? Chapter 103: Non-Hodgkins lymphoma. Other side effects can include feeling tired, rash, fever, and headache. More serious side effects include infection, fluid collection in the lungs, around the heart, or in the abdomen (belly), very low blood counts, and very severe skin reactions when out in the sun. Methods: Chimeric Antigen Receptor (CAR) T-cell therapy involves genetic modification of patient's autologous T-cells to express a CAR specific for a tumor antigen, following by ex vivo cell expansion and re-infusion back to the patient. 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. This site needs JavaScript to work properly. Common side effects include abnormal liver function tests, low blood counts, feeling tired, rash, nausea, and muscle and joint pain. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. A 54% (7/13) ORR (including 5 CRs and 2 PRs) . Clipboard, Search History, and several other advanced features are temporarily unavailable. 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 not a BCMA-directed agent. National Comprehensive Cancer Network (NCCN). The relevance and the necessary length of interruption to reverse T-cell exhaustion is unknown. The use of adapter CAR T cells is aimed at combining the benefits of BiTE molecules with the power of ex vivoactivated CAR T cells. It is approved for use in patients with follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia. Become a volunteer, make a tax-deductible donation, or participate in a fundraising event to help us save lives. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. The American Cancer Society is a qualified 501(c)(3) tax-exempt organization. Age was a particularly variant factor between study cohorts. How do you approach sequencing in your own practice? 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. CAR T cell therapy is also built off a monoclonal antibody known as chimeric antigen receptor (CAR). This approach enables escalation of the titrated BiTE dose while maintaining a favorable safety profile. Park et al22 reported on long-term follow-up of CD19-CD28 CAR T cells in a pediatric BCP-ALL population (n = 53). The future is going to have personalized medicine. The https:// ensures that you are connecting to the Nonetheless, the use of such new drugs to treat solid tumors is not . #mmsm. We are going to be individualizing precision medicine and treating patients specific DNA abnormalities in their myeloma cells. Physician Data Query (PDQ). Your doctor will check your blood cell counts regularly during your treatment. 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. Thus, the overall safety profile appears to be better for BiTE molecules than for CAR T cells. Accessed at https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf on May 2, 2018. Low blood cell counts: This drug might lower your blood cell counts, which can increase your risk of infections or bleeding. Philadelphia, Pa: Elsevier; 2014. Accessed at https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf on May 2, 2018. Amandeep Godara, MBBS, of @huntsmancancer, discusses important patient factors to consider when deciding between a CAR T-cell therapy vs bispecific antibody in relapsed/refractory multiple myeloma. As stated, the upregulation of immune checkpoint molecules is an escape mechanism common to both BiTE and CAR T-cell therapy, and these can be expressed on both activated and exhausted T cells. Initial expansion of infused CAR T cells DREAMM-3 through DREAMM-16 [are trials] that are evaluating a variety of other agents to be added to belantamab mafodotin. This is exciting for patients and their families. This opens up a wide avenue of patients with multiple myeloma who may have exhausted all other potential treatments. This syndrome is caused when the transferred T cells, or other immune cells responding to the new T cells, release a large amount of cytokines into the blood. We can control a patients disease for an unbelievably extended period of time. IgE antibodies targeting cancer antigens can be used for immunotherapy. Given this risk, the company that makes these drugs puts restrictions on access to them to prevent women who are or might become pregnant from being exposed to them. Your doctor may check your blood for signs of an old hepatitis B infection before you start treatment. Unable to load your collection due to an error, Unable to load your delegates due to an error, The structure of different types of mAbs. 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. Although they are not currently the standard of care, I anticipate within the next 5 years that they will become the standard of care potentially up front, as well as in the relapsed/refractory settings for patients with multiple myeloma. The emerging bispecific antibodies (BsAbs), which recruit T cells to tumor cells, exemplified by bispecific T cell engagers (BiTEs), have facilitated the development of tumor immunotherapy. Most reactions are mild, such as itching, chills, fever, nausea, rashes, fatigue, and headaches. 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. OncLive: What makes BCMA a logical target in multiple myeloma? It is a little bit confusing because, in theory, we could use [belantamab mafodotin] in the second- or third-line settings. The American Cancer Society medical and editorial content team. 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. Instead, selinexor is directed against a specific mechanism in the nucleus of the myeloma cells [called XPO1]. This drug is infused into a vein (IV), usually 3 times a week for up to 12 weeks. Version 3.2018. Patients get CAR T cells on day 1 and they may not need therapy for 1 or 2 years, perhaps longer. The most common side effects are fever, chills, nausea, and rashes. Lancet Oncol. [Both] are BCMA-directed therapies. Neelapu SS, Locke FL, Bartlett NL, et al. Are BiTEs better than CAR T approaches? However, adapter kinetics, target antigen affinities, and antigen sinks are challenges that need to be overcome.36. BiTEs provide the advantage of flexibility of targeting multiple antigens simultaneously and sequentially and can be used in combination with chemotherapy, small molecules, and immunomodulatory drugs, such as checkpoint inhibitors. In the vast majority of patients, this is very minor and presents as blurred vision or dry, scratchy eyes. Federal government websites often end in .gov or .mil. Clearly, intertrial comparisons are problematic per se and are further complicated by differences in toxicity grading systems,14 trial design, inclusion and exclusion criteria (including disease entities [TOWER and JULIET (r/r ALL vs ZUMA-1 and ELIANA (r/r diffuse large B-cell lymphoma [DLBCL])]), and patient cohorts (eg, average age within the JULIET trial was 11 years of age, whereas the other trials were conducted on adults). Finally, both treatment platforms are associated with high financial toxicity. Lisocabtagene maraleucel (Breyanzi, also known as liso-cel) is approved to treat adults with diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and follicular lymphoma grade 3B, after at least one other kind of treatment has been tried. Many trials have looked at triplets versus doublets, and essentially all of them show that triplets are superior to doublets in the frontline and relapsed/refractory settings. Right now, we have the option to make this a chronic disease in the same way high blood pressure or diabetes [are chronic diseases]. Ultimately, this will result in superior quality of life (QOL) for those patients who are going to get continuous therapy. However, adverse events of grade 3 or higher occurred in 87% of patients treated with blinatumomab in the TOWER trial, which is lower than observed in the ZUMA-1 trial (95%) and similar to those rates in the JULIET (89%) and ELIANA (88%) trials. The antibody acts like a homing signal, bringing the chemo drug to lymphoma cells, where it enters the cells and kills them. The aim of checkpoint inhibitors is to release the brakes that block the action of the immune system against the tumor. Currently, patients with stage I disease have a life expectancy that exceeds 10 to 15 years versus 2.5 years [when I first started]. Most of the [newer treatments] are more sensitive and specific to myeloma cells with much less bystander effect. Several monoclonal antibodies are now used to treat non-Hodgkin lymphoma (NHL). With CAR T cells, patients get their therapy, get their response, and may not require treatment for an extended period of time. Selinexor (Xpovio) is another drug that was recently approved for patients who have had 4 prior lines of therapy. 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. They are tolerated better and their efficacy is better than conventional chemotherapy. A third very common toxicity of CAR T-cell therapy consists of prolonged and severe cytopenia that can predispose for severe infectious complications.15 CAR T-cellassociated hematotoxicity is related to mandatory lymphodepleting chemotherapy prior to CAR T-cell infusion and immunomodulation through CAR T cells. These include: These drugs are given into a vein (IV), often over several hours. National Library of Medicine Because of these kinds of reactions, drugs to help preventthem aregiven before each infusion. 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. In this treatment, immune cells called T cells are removed from the patients blood and altered in the lab to have specific receptors (called chimeric antigen receptors, or CARs) on their surface. This process helps the T cells . For patients who respond [to belantamab mafodotin], the duration of response exceeds 11 months. In the context of CAR T cells, in vitro studies have demonstrated the reversal of T-cell exhaustion through drug-induced regulation. Cytokines are immune substances that have many different functions in the body. There will certainly be a lot of competition for belantamab mafodotin in this niche [setting of patients who received at least 4 prior therapies]. Help us end cancer as we know it,for everyone. Bispecific proteins (recombinant proteins that simultaneously bind 2 different antigens) and chimeric antigen receptors (CARs) facilitate T-cellmediated killing of malignant cells by redirecting autologous T lymphocytes to cell-surface antigens on cancer cells. Contribution: M.S. 2010;11:753762. Version 5.2018. It is useful in some cases of SLL/CLL and some types of peripheral T-cell lymphomas. When we combine belantamab mafodotin with other active agents with different mechanisms of action, we can see superior response rates and remission durations. Our group is heavily biased toward stem cell transplants, which is considered standard of care throughout the world. Monoclonal antibodies (mAbs) and chimeric antigen receptor (CAR) T cells are two branches of cancer immunotherapy. Finally, CAR-T cells are infused into the patients bloodstream to kill the tumor cells, Five generations of CAR-T cells. 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. Optimized CAR T-cell logistics, including an increase in the number and sites of production, as well as changes in ex vivo culture time, will most likely shorten the time from harvesting to infusion.9 In contrast, BiTEs are recombinant proteins that can be manufactured in large quantities without interpatient variability and can be rapidly used once the indication has been determined by the clinician, independent of peripheral lymphocyte counts. The relevance of blinatumomab prior to treatment with CD19 CAR T cells is still under investigation with conflicting reports emerging. The data strongly support the use of blinatumomab in MRD-positive patients with BCP-ALL. We need combination therapies that have different mechanisms of action. -, Martin FL, Martinez EZ, Stopper H, Garcia SB, Uyemura SA, Kannen V. Increased exposure to pesticides and colon cancer: Early evidence in Brazil. 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 . -, Veisi Malekshahi Z, Hashemi Goradel N, Shakouri Khomartash M, Maleksabet A, Kadkhodazadeh M, Kardar GA, et al. The Case for CAR Martin explained that CAR T-cell therapy is human T lymphocytes in which a gene has been inserted, typically using a retrovirus or adenovirus, and the gene has an extracellular domain that binds to the cell of interest, a transmembrane domain, and an intracellular signaling domain. 10th ed. This brings the two together, which helps the immune system attack the lymphoma cells. However, the BiTE platform offers a higher flexibility for combinatorial and sequential approaches from a toolbox of targeting and immunomodulatory antibody constructs. 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. The strategy of combining targeting tumor antigens has also been applied to chimeric antigen receptor (CAR) T cell therapy and is a promising immunotherapy for several malignancies, such as . 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.