High Rates of Expression Paint CEACAM1 as a Potential Therapeutic Target in Mantle Cell Lymphoma

Although CEACAM1 expression is not ubiquitous across non-Hodgkin lymphoma subtypes and other hematologic malignancies, its high frequency of expression in patients with mantle cell lymphoma (MCL) points to this protein as a potential therapeutic target for this patient population.¹

In a retrospective study, investigators analyzed cases of lymphoma (n = 164), multiple myeloma (n = 35), and plasmacytomas (n = 2); the lymphoma group included patients with MCL (n = 30), diffuse large B-cell lymphoma (DLBCL; n = 82), marginal zone lymphoma (MZL; n = 22), and small lymphocytic lymphoma (SLL; n = 30).

Findings published in the American Journal of Clinical Pathology showed that CEACAM1 was expressed in 90% of patients with MCL compared with 35% of those with all other lymphoma subtypes combined (P < .0001). CEACAM1 expression rates were 23% in DLBCL, 36% in MZL, and 67% in SLL. The expression rate was 66% for multiple myeloma and 100% for plasmacytomas.

Given the aggressive nature of MCL vs other lymphoma subtypes and the frequency of relapse for this patient population, a target like CEACAM1 could represent a targeted strategy to specifically address treatment for this population.

“In this situation, this is a potential target that does not necessarily have high expression outside of malignant B cells,” study co-author Tycel Phillips, MD, said in an interview with OncLive^®. “Its high expression level in MCL allows for potential targeting, whether it be an antibody-drug conjugate [ADC] or bispecific antibody.”

Phillips is an associate professor in the Department of Hematology and Hematopoietic Cell Transplantation in the Division of Lymphoma at City of Hope in Duarte, California.

What is CEACAM1?

CEACAM1 is a member of the carcinoembryonic antigen (CEA) family of immunoglobulin-like transmembrane proteins that are typically expressed across B and T lymphocytes, natural killer cells, granulocytes, epithelial cells, and certain endothelial cells. The molecule serves as a cell membrane receptor that transduces extracellular signals into the cytoplasm. Based on these signaling functions, CEACAM1 has been implicated in apoptosis, angiogenesis, cell proliferation, cell motility, and immune T-cell tolerance.

“[With] potentially some high expression in patients who have progressed on BTK inhibitors, [CEACAM1 targeting] could and would slide nicely into the [MCL] space, given what we’ve seen with the BTK inhibitors moving further and further up in the lines of treatment,” Phillips said. “[We could reach a point where] maybe all patients will see a BTK inhibitor within their first 2 [lines] of treatment, so that does shift up other sorts of treatment modalities substantially in this space. Having new options [is] 100% needed, [along with] new targets to fill the void.”

What past data were reported for targeting CEACAM1 in oncology?

Currently, no agents targeting CEACAM1 are being evaluated in patients with MCL, but previous research has focused on this protein in other tumor types.

Findings from a phase 1/2 trial (NCT04731467) presented at the 2024 American Society of Clinical Oncology Annual Meeting showed that treatment with the CEACAM1-blocking monoclonal antibody CM24 in combination with nivolumab (Opdivo) and chemotherapy led to a median progression-free survival of 3.8 months (95% CI, 1.8-5.0) in patients with previously treated locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC; n = 16) compared with 1.9 months (95% CI, 0.9-3.6) for those treated with chemotherapy alone (n = 15; HR, 0.72; 95% CI, 0.33-1.60).² The median overall survival values were 7.72 months (95% CI, 4.00-8.11) vs 5.62 months (95% CI, 3.22-7.89), respectively (HR, 0.74; 95% CI, 0.31-1.77). The CM24-based regimen produced an overall response rate of 25.0% and a disease control rate of 62.5%; these respective rates for chemotherapy alone were 6.7% and 40.0%.

The investigators noted that the CM24-based regimen was well tolerated.

Furthermore, in preclinical evaluation, the CEACAM1-targeting monoclonal antibody 3C11 showed synergy with anti–PD-1 immunotherapy in non–small cell lung cancer cell lines, achieving 85% tumor growth inhibition in vivo compared with 18% for anti–PD-1 therapy alone.³

Along with past preclinical and clinical experience across different tumor types, Phillips cited advances in drug development as a reason for optimism about targeting CEACAM1 in MCL.

“With the technology we have, it allows you to attach multiple different payloads with ADCs or bispecific antibodies, as long as the [target] expression is there,” Phillips said. “A lot of treatments can develop into [CAR T-cell therapy], bispecific antibodies, and ADCs, which is where a lot of the more recent research is heading with some of these newer [targets] or even some of these older targets that are being resurrected.”

What is next for investigating CEACAM1 in MCL?

Although retrospective data showed high rates of CEACAM1 expression in patients with MCL, Phillips and colleagues cautioned that the heterogeneous biology of MCL, as well as SLL and MZL, could limit the interpretation of this expression across the full patient population. However, Phillips underscored that in MCL, or even other lymphoma subtypes in which CEACAM1 expression has not been as common, the further evaluation of CEACAM1 opens the door for a potential therapeutic avenue.

“As long as there’s some expression level in some of these other subtypes, ([for example, we even] have some minor subexpression in LBCL), it does allow some opportunities for drug targeting,” Phillips said. “[For example, if] we look specifically at LBCL, if you start getting to the third-line setting [and beyond], where patients have difficult-to-treat disease, you’re usually trying to grab whatever treatment you can. [Our data on] the expression level [of CEACAM1 in LBCL] are similar to what we see with CD30 expression, which hasn’t necessarily stopped the approval of certain agents within this space.”

One key point Phillips highlighted is that determining the level of CEACAM1 expression could serve as an enrollment cutoff for potential clinical trials, noting that studies across oncology have used different target expression thresholds for enrollment when testing targeted agents.

Beyond that, further research into CEACAM1-targeting approaches could ultimately lead to additional treatment options for MCL.

“Given that there’s been an influx of CD20- and CD19-directed treatments, one of the concerns we have is expression loss,” Phillips concluded. “If you get a patient who doesn’t [express] CD19 or CD20, that eliminates approximately 99% of the treatment options we have. If these patients would have subsequently also [progressed on] a BTK inhibitor, you pretty much have a patient with limited to no treatment options. CEACAM1 would then fill in the gap because at that point, it gives us another target to aim our agents at.”

References

1. Sethapati VR, Ngo V, Danilov A, et al. CEACAM1 expression by immunohistochemistry in B-cell lymphomas and plasma cell myeloma. Am J Clin Pathol. 2026;165(6):aqag078. doi:10.1093/ajcp/aqag078
2. Macarulla T, Cecchini M, Garcia-Carbonero R, et al. Interim results of the randomized phase 2 cohort of study FW-2020-01 assessing the efficacy, safety and pharmacodynamics of CM24 in combination with nivolumab and chemotherapy in advanced/metastatic pancreatic cancer. J Clin Oncol. 2024;42(suppl 17):LBA4143. doi:10.1200/JCO.2024.42.17_suppl.LBA4143
3. Zhao L, Li T, Zhou Y, Wang P, Luo L. Monoclonal antibody targeting CEACAM1 enhanced the response to anti-PD1 immunotherapy in non-small cell lung cancer. Int Immunopharmacol. 2024;143(Pt 2):113395. doi:10.1016/j.intimp.2024.113395