T-Cell Engagers Emerge Across Cancer Settings

Targeted Therapies in OncologyJuly 1, 2023
Volume 12
Issue 9
Pages: 61

Since blinatumomab was first approved in 2014 for relapsed/refractory acute lymphoblastic leukemia, the field has seen rapid progress. Now, a growing number of BiTEs are under development for different solid tumors and hematologic malignancies.

Martha P. Mims, MD, PhD Professor and Chief Medicine Hematology & Oncology Associate Director of Clinical Research Dan L Duncan Comprehensive Cancer Center Baylor College of Medicine Houston, TX

Martha P. Mims, MD, PhD

Professor and Chief Medicine

Hematology & Oncology

Associate Director of Clinical Research

Dan L Duncan Comprehensive Cancer Center

Baylor College of Medicine

Houston, TX

Bispecific T-cell engagers(BiTEs) are a group of bispecific antibodies that target 1 tumor antigen and 1 immune-related molecule, CD3, promoting the activity of tumor-specific cytotoxic T cells. Since blinatumomab (Blincyto), targeting CD19/CD3, was first approved in 2014 for relapsed/refractory (R/R) acute lymphoblastic leukemia, the field has seen rapid progress. Now, a growing number of BiTEs are under development for different solid tumors and hematologic malignancies.

A common adverse event of bispecific antibody immunotherapy is cytokine release syndrome (CRS), a potentially life-threatening complication in which activated immune cells release many cytokines into the bloodstream. Another potential complication is the immune effector cell– associated neurotoxicity syndrome.

“Management of these adverse events takes training and requires the use of drugs that may not be available at all hospitals. For the more difficult drugs, I can see that the first cycle might be given in an academic hospital and safer subsequent doses out in the community,” Martha P. Mims, MD, PhD, professor of medicine and chief of hematology and oncology at Baylor College of Medicine in Houston, Texas, said in an interview with Targeted Therapies in Oncology.

Bispecific engineering platforms enable the rapid proof-of-concept testing of various combinations and have been created to accelerate the development of molecules with high efficacy and low toxicity.1-3 One goal is to extend the half-life of BiTEs through the fusion of a common BiTE molecule to an fragment crystallizable (Fc) domain. One example is AMG 701, which targets the B-cell maturation antigen (BCMA) in multiple myeloma (MM).

Most BiTE antigen targets for hematologic malignancies are tumor specific. CD19 is an important target for B-cell malignancies, BCMA is expressed in MM, and CD33 is expressed in myeloid leukemias and myelodysplastic syndrome (MDS). The FMS-like tyrosine kinase 3 (FLT3) antigen is also expressed in myeloid leukemias and MDS, but many other combinations are in early clinical trials, as well.3 The following presents a nonexhaustive description of some approaches.

Acute Myeloid Leukemia

New therapies are needed for acute myeloid leukemia (AML), as the 5-year survival rate is still less than 50% and even lower when associated with certain genetic abnormalities.4 The development of immunotherapies for AML has been difficult due to the lack of ideal target antigens. Currently used target antigens that are combined with CD3 include CD33, CD123, and FLT3, which are all expressed on AML blasts and leukemic stem cells.

CD33/CD3 BiTEs

The Children’s Oncology Group is conducting a phase 1 dose escalation trial in pediatric patients with R/R AML (NCT05077423); results are pending.

CD123/CD3 BiTEs

Vibecotamab (XmAb14045) showed an objective response rate (ORR) of 14% in a heavily pretreated patient population, and 58% experienced CRS (85% grade 1-2, 15% grade ≥ 3).5 A phase 2 study (NCT05285813) is currently underway.


A phase 1 trial of CLN-049 (NCT05143996) is currently enrolling patients with R/R AML or MDS, based on promising preclinical results.

Multiple Myeloma

MM is another disease that generally remains incurable. The elderly patient population is often unable to tolerate more aggressive chemotherapy or treatment with chimeric antigen receptor (CAR) T cells. BiTE therapy mainly takes advantage of BCMA.7


• On October 25, 2022, the FDA granted accelerated approval to teclistamab-cqyv (Tecvayli) for adult patients with R/R MM who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. This was based on 2 studies (NCT03145181 and NCT04557098) that showed an ORR of 63%, including a complete response (CR) in 39.4% of patients and a median progression-free survival (PFS) of 11.3 months. CRS occurred in 72.1% (less than 1% of grade 3 or higher), and hematologic toxicities occurred in more than half the patients.8 Additional trials in patients with other hematologic malignancies are ongoing.

• REGN5459 has also shown positive results in phase 1/2 clinical trials in patients with R/R MM , with an ORR of 90.5% at the highest dose level, including 61.9% with a CR. Although greater than 50% of patients experienced CRS, 87% were of grade 1 and none were of grade 3 or higher. the lower toxicity rate appears to be due to the decreased binding affinity to T cells.9

• REGN5458 (linvoseltamab) is also garnering attention. In phase 1/2 studies, the ORR with a dose of 200 mg or greater was 75% and responses deepened over time, with 37.5% or greater of patients with CR. REGN5458 was associated with CRS in 47.9% of patients (grade 3 in 0.6%)10

• AMG 701 has an extended half-life, allowing for once-weekly intravenous infusions, and a subcutaneous version is under development. The ORR in a heavily pretreated population was 36% at doses of 3 mg to 12 mg; with earlier dose escalation to 9 mg, it increased to 83%. Mostly low-grade CRS occurred in 61% of patients, and reversible neurotoxicity was seen in a minority.11

CD38/CD3 BiTEs

Early toxicity data with the CD38/CD3 product ISB 1342 showed good tolerance at the dose levels evaluated, with only moderate grade CRS. Dose escalation continues, with additional dose cohorts accruing.12


GPRC5D is an orphan receptor that is expressed in malignant plasma cells. Talquetamab, given either intravenously or subcutaneously, has a very promising profi le, with an ORR of 70% for a median duration of 10.2 months. Adverse events, including CRS, skin-related events, and dysgeusia, were common but primarily low grade.13 Several phase 3 studies, both in R/R and newly diagnosed patients with MM, are currently ongoing.

Non-Hodgkin Lymphoma

Several approaches are being explored for aggressive or relapsed lymphoma, both in the choice of the immune target and the tumor antigen. CD19/CD3 BiTEs

• Blinatumomab was approved several years ago for the treatment of relapsed acute lymphocytic leukemia and has shown efficacy in R/R aggressive B-cell non-Hodgkin lymphoma. An open-label phase 2/3 study (NCT01207388) resulted in an ORR after 12 weeks of 37%, including a 22% CR rate. However, toxicity may be a problem, as grade 3 or greater adverse events were seen in 71% of patients, with grade 3 CRS in 1 patient and grade 3 neurologic events in 24%.14

• TNB-486 is a novel BiTE that incorporates a unique anti-CD3 moiety that binds to T cells with a low affinity, possibly reducing the occurrence of CRS. In addition, it has a long half-life that is suitable for intermittent administration. In a small study (NCT04594642) of 18 evaluable patients, the ORR at 800 µg or higher was 72%, and the CR rate was 61%. Although CRS occurred in 59%, none of them were higher than grade 2 and none occurred after cycle 1.15

CD20/CD3 BiTEs

• Epcoritamab-bysp (Epkinly), administered subcutaneously, was approved in May 2023 for R/R diffuse large B-cell lymphoma (DLBCL). In the phase 1 EPCORE NHL-1 trial (NCT03625037) of patients with R/R DLBCL who had received at least 2 prior lines of systemic therapy, it was administered as a 1-mL subcutaneous injection in 28-day cycles. The ORR in the patients who received greater than 48 mg was 91%, with a median duration of response of 12 months.16 In the phase 1/2 EPCORE NHL-2 trial (NCT04663347), patients who had failed or were ineligible for stem cell transplant initially received epcoritamab weekly, then every 2 weeks, and 4 weeks together with rituximab, gemcitabine, and oxaliplatin every 2 weeks. The 25 evaluable patients achieved an ORR of 92% (up to 6.9 months), with an acceptable toxicity profile.17

• Mosunetuzumab-axgb (Lunsumio) was recently approved for R/R follicular lymphoma18 and is currently being evaluated in a phase 1/2 trial (NCT03677154) of elderly/unfit patients with previously untreated DLBCL. Initial results after a median follow-up of 23.3 months resulted in best ORR and CR rates of 56% and 43%, respectively, with a median duration of CR of 15.8 months and a 12-month PFS rate of 39%. No grade 3 or greater CRS occurred, and no patient had neurologic toxicity.19

• Glofitamab is a CD20/CD30 BiTE with a 2:1 configuration favoring CD20 binding sites to increase potency. In a phase 2 study (NCT03075696) of patients with R/R DLBCL after at least 2 lines of therapy, a CR was achieved in 39% and maintained in most patients for 12 months, with a PFS of 37%. Discontinuation of glofi tamab due to adverse events occurred in 9%, and grade 3 or greater CRS and neurologic events in 4% and 3% of patients, respectively.20 The FDA recently accepted glofi tamab treatment for R/R DLBCL for priority review.21

• Odronextamab (REGN1979)is a fully human immunoglobulin G4–based CD20/CD3 BiTE modifi ed for reduced Fc binding. A phase 2 trial (NCT03888105) of adult patients with R/R DLBCL evaluated different escalation schemas to minimize toxicity. After a median follow-up of 17.1 months, the ORR and CR rate were 53% and 37%, respectively, and were consistent across high-risk subgroups. CRs were durable, and the probability of an ongoing CR at 9 months was estimated at 73%. The toxicity profile was manageable, with only low-grade CRS and neurotoxicity in a minority of patients.22

BiTe or CAR T Cell?

Although CAR T-cell therapy requires only a single infusion, most treatments are done in the inpatient setting, even possibly in intensive care units, and the patient is required to stay close to the specialized treatment center for several weeks after the infusion. Most BiTEs are given intravenously, often on 2 or more subsequent days, and must be repeated for several cycles but can be administered in the clinic. The most promising approach is not one or the other but a possible combination to provide the best survival advantage and quality of life to these patients with often difficult-to-treat cancers.

“I think the most exciting new developments involve B-cell lymphomas— glofi tamab [for DLBCL], mosunetuzumab [for follicular lymphoma], and epcoritamab [for DLBCL]. These drugs have response rates up to 80% to 90% and CR rates as high as 55% to 60%. These are hard numbers to touch with traditional chemotherapies for [R/R] disease,” Mims said. “Similarly for myeloma, teclistamab has shown response rates of more than 60% in patients refractory to 3 classes of therapy and CR rates of nearly 40%, with some patients showing no minimal residual disease. This is an incredible step in myeloma. These drugs are amazing of-fthe-shelf immunotherapies that ‘cut the line’ for many patients waiting for costly CAR T-cell therapy.”

1. Mai J, Caldwell K, DeVorkin L, et al. Identifying T-cell engagers with optimal potency and cytokine-release profiles with a diverse panel of CD3-binding antibodies. Cancer Research. 2023;83(suppl 7):1886. doi:10.1158/1538-7445. Am2023-1886
2. Tortora D, Bergqvist P, Leung GP, et al. Breaking barriers to access intracellular targets with T-cell engagers: discovery of diverse, developable, and ultra-specific antibodies against a MAGE-A4 pMHC. Cancer Research. 2023;83(suppl 7):1891. doi:10.1158/1538-7445.Am2023-1891
3. Einsele H, Borghaei H, Orlowski RZ, et al. The BiTE (bispecific T-cell engager) platform: development and future potential of a targeted immuno-oncology therapy across tumor types. Cancer. 2020;126(14):3192-3201. doi:10.1002/cncr.32909
4. Stubbins RJ, Francis A, Kuchenbauer F, Sanford D. Management of acute myeloid leukemia: a review for general practitioners in oncology. Curr Oncol. 2022;29(9):62456259. doi:10.3390/curroncol29090491
5. Ravandi F, Bashey A, Stock W, et al. Complete responses in relapsed/refractory acute myeloid leukemia (AML) patients on a weekly dosing schedule of vibecotamab (XmAb14045), a CD123 x CD3 T cell-engaging bispecific antibody; initial results of a phase 1 study. Blood. 2020;136(suppl 1):4-5. doi:10.1182/blood-2020-134746
6. Meetze K, Mehta NK, Pfl uegler M, et al. CLN-049 is a bispecifi c T cell engaging IgG-like antibody targeting FLT3 on AML cells. Cancer Research. 2022;82(suppl 12):2078. doi:10.1158/1538-7445.Am2022-2078
7. Shah N, Chari A, Sco E, Mezzi K, Usmani SZ. B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches. Leukemia. 2020;34(4):985-1005. doi:10.1038/s41375-020-0734-z
8. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387(6):495-505. doi:10.1056/NEJMoa2203478
9. Suvannasankha A, Kapoor P, Pianko MJ, et al. Safety and efficacy from the phase 1/2 fi rst-in-human study of REGN5459, a BCMA×CD3 bispecific antibody with low CD3 affinity, in patients with relapsed/refractory multiple myeloma. Presented at: American Association for Cancer Research Annual Meeting; April 14-19, 2023; Orlando, FL. https://www.abstractsonline.com/pp8/#!/10828/presentation/10253
10. Bumma N, Richter J, Brayer J, et al. Updated safety and efficacy of REGN5458, a BCMAxCD3 bispecific antibody, treatment for relapsed/refractory multiple myeloma: a phase 1/2 first-in-human study. Blood. 2022;140(supple 1):10140-10141. doi:10.1182/blood-2022-159969
11. Harrison SJ, Minnema MC, Lee HC, et al. A phase 1 first in human (FIH) study of AMG 701, an anti-B-cell maturation antigen (BCMA) half-life extended (HLE) BiTE (bispecifi c T-cell engager) molecule, in relapsed/refractory (RR) multiple myeloma (MM). Blood. 2020;136(suppl 1):28-29. doi:10.1182/ blood-2020-134063
12. Mohan SR, Chase CC, Berdeja JG, et al. Initial results of dose escalation of ISB 1342, a novel CD3xCD38 bispecific antibody, in patients with relapsed / refractory multiple myeloma (RRMM). Blood. 2022;140(suppl 1):7264-7266. doi:10.1182/blood-2022-157525
13. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-cell-redirecting GPRC5D bispecifi c antibody for multiple myeloma. N Engl J Med. 2022;387(24):2232-2244. doi:10.1056/NEJMoa2204591
14. Coyle L, Morley NJ, Rambaldi A, et al. Open-label, phase 2 study of blinatumomab as second salvage therapy in adults with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Leuk Lymphoma. 2020;61(9):2103-2112. doi:10.10 80/10428194.2020.1759055
15. Hou JZ, Jacobs R, Cho SG, et al. Interim results of the phase 1 study of Tnb-486, a novel CD19xCD3 T-cell engager, in patients with relapsed/refractory (R/R) B-NHL. Blood. 2022;140(suppl 1):1474-1475. doi:10.1182/blood-2022-166385
16. Hutchings M, Mous R, Clausen MR, et al. Subcutaneous epcoritamab induces complete responses with an encouraging safety profile across relapsed/refractory B-cell non-hodgkin lymphoma subtypes, including patients with prior CAR-T therapy: updated dose escalation data. Blood. 2020;136(suppl 1):45-46. doi:10.1182/blood-2020-133820
17. Wahlin BE, Brody J, Phillips T, et al. Subcutaneous epcoritamab with GemOX induced high response rates in patients with relapsed/refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplant. HemaSphere. 2022;6:1099-1100. doi:10.1097/01.HS9.0000847716.29326.a8
18. Budde LE, Assouline S, Sehn LH, et al. Single-agent mosunetuzumab shows durable complete responses in patients with relapsed or refractory B-cell lymphomas: phase I dose-escalation study. J Clin Oncol. 2022;40(5):481-491. doi:10.1200/JCO.21.00931
19. Olszewski AJ, Avigdor A, Babu S, et al. Mosunetuzumab monotherapy continues to demonstrate promising effi cacy and durable complete responses in elderly/unfit patients with previously untreated diff use large B-cell lymphoma. Blood. 2022;140(suppl 1):1778-1780. doi:10.1182/ blood-2022-157768
20. Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofi tamab for relapsed or refractory diffuse large b-cell lymphoma. N Engl J Med. 2022;387(24):2220-2231. doi:10.1056/NEJMoa2206913
21. FDA grants priority review to Genentech’s bispecific antibody glofitamab for people with relapsed or refractory large B-cell lymphoma. News release. Genentech. January 5, 2023. Accessed June 1, 2023. h ps://bit.ly/45MSoqK
22. Kim WS, Kim TM, Cho SG, et al. Odronextamab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): results from a prespecified analysis of the pivotal phase II study ELM-2. Blood. 2022;140(suppl 1):1070-1071. doi:10.1182/blood-2022-158406
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