Targeting the 5T4 oncofetal glycoprotein with an antibody drug conjugate (A1mcMMAF) improves survival in patient-derived xenograft models of acute lymphoblastic leukemia

Abstract

Outcome in childhood acute lymphoblastic leukemia is prognosticated from levels of minimal residual disease after remission induction therapy. Higher levels of minimal residual disease are associated with inferior results even with intensification of therapy, thus suggesting that identification and targeting of minimal residual disease cells could be a therapeutic strategy. Here we identify high expression of 5T4 in subclonal populations of patient-derived xenografts from patients with high, post-induction levels of minimal residual disease. 5T4-positive cells showed preferential ability to overcome the NOD-scidIL2Rγnull mouse xenograft barrier, migrated in vitro on a CXCL12 gradient, preferentially localized to bone marrow in vivo and displayed the ability to reconstitute the original clonal composition on limited dilution engraftment. Treatment with A1mcMMAF (a 5T4-antibody drug conjugate) significantly improved survival without overt toxicity in mice engrafted with a 5T4-positive acute lymphoblastic leukemia cell line. Mice engrafted with 5T4-positive patient-derived xenograft cells were treated with combination chemotherapy or dexamethasone alone and then given A1mcMMAF in the minimal residual disease setting. Combination chemotherapy was toxic to NOD-scidIL2Rγnull mice. While dexamethasone or A1mcMMAF alone improved outcomes, the sequential administration of dexamethasone and A1mcMMAF significantly improved survival (P=0.0006) over either monotherapy. These data show that specifically targeting minimal residual disease cells improved outcomes and support further investigation of A1mcMMAF in patients with high-risk B-cell precursor acute lymphoblastic leukemia identified by 5T4 expression at diagnosis.

Combination Treatment with an Antibody–Drug Conjugate (A1mcMMAF) Targeting the Oncofetal Glycoprotein 5T4 and Carboplatin Improves Survival in a Xenograft Model of Ovarian Cancer

“…The effectiveness of ADCs depends on numerous factors including tumour expression levels of the target antigen, as well as the ability of tumour cells to internalise and cleave the conjugated drug and undergo apoptosis in response. More recently, it has been demonstrated that this activity can be further enhanced by concurrent administration of other chemotherapeutics [28, 29]. Our study confirms that 5T4 is expressed by all histotypes of EOC, but particularly in women with high-grade serous carcinoma and supports the findings demonstrated in other published series [11–13].…”

“…This is consistent with the hypothesis that 5T4 expression may have a functional role in relapse and/or metastasis. Selective elimination of tumour-initiating cells expressing 5T4 using ADCs was shown to be effective at prolonging survival in mouse models of both non small cell lung carcinoma (NSCLC) and pre-B acute lymphoblastic leukemia [26–28]. Demonstrating similar effects in EOC, a condition in which most women will relapse following their initial surgery and chemotherapy, could offer additional options for disease control.…”

“…A1mcMMAF has been shown to be rapidly internalised on binding of the antibody portion and to have potent in vivo activity in a variety of tumour models [26] leading to the initiation of a phase I dose-escalation study [25]. Recent work has identified that combining a 5T4 ADC with various other chemotherapeutics enhances its effects on survival [28, 29]. These data support further investigation of A1mcMMAF in combination with chemotherapy in other cancers.…”

Antibody-Drug Conjugates (ADC) Against Cancer Stem-Like Cells (CSC)—Is There Still Room for Optimism?

“…The potential of PF-06263507 for the treatment of hematological malignancies was also investigated (66), given the finding that 5T4 was overexpressed on minimal residual acute lymphoblastic leukemia (ALL) cells. PF-06263507 significantly improved survival in mice engrafted with 5T4 + patient-derived ALL cells, and even more so in combination with chemotherapy or dexamethasone.…”

Oncolytic virus and PD-1/PD-L1 blockade combination therapy

“… 63 These viruses were designed to express human 5T4 oncofetal glycoprotein, an N-glycosylated transmembrane protein associated with differentiating embryonic stem cells and tumor-initiating cells of various carcinomas. 68 Dual virus therapy could completely protect mice challenged with B16 tumor cells (which overexpress murine 5T4) when administered as a vaccine, but they were only modestly effective against established tumors. Combining oncolytic adenovirus, MVA and anti-PD-1 antibody resulted in stronger induction of 5T4-specific T-cell responses and significantly increased overall survival.…”