“Dar”-ing to target CD38 in T-ALL

In this issue of Blood, Bride et al show that CD38 is expressed on pediatric T-cell acute lymphoblastic leukemia (T-ALL) at the time of diagnosis, after induction treatment, and at the time of relapse and that targeting CD38 with the monoclonal antibody daratumumab shows great efficacy in multiple patient-derived xenograft (PDX) models of T-ALL.¹ 

T-ALL is a malignant neoplasm of the bone marrow representing 20% of ALL diagnoses and is particularly common in adolescents and young adults. In pediatric studies, patients with T-ALL have not yet achieved the same extremely high survival rates as children with B-cell ALL (B-ALL) and are still routinely allocated to the more intensive high-risk arms of pediatric clinical trials.²  Early T-precursor ALL (ETP-ALL) represents a recently identified subgroup of T-ALL characterized by a unique gene expression signature and by inferior outcomes compared with non–ETP-ALL.³  Although T-ALL is potentially curable with standard therapy, patients with relapsed disease have poor outcomes with less than 10% surviving long term.⁴  Few therapies exist for relapsed disease. Currently, nelarabine and liposomal vincristine are the only US Food and Drug Administration (FDA)–approved treatment of relapsed/refractory T-ALL.⁴  This is in contrast to a number of targeted immunotherapies for B-ALL, including rituximab (CD20-positive disease) and several newer agents including CD19-specific chimeric antigen receptor (CAR) T cells, blinatumomab (CD19-positive disease), and inotuzumab ozogamicin (CD22-positive disease), all of which have high single-agent response rates in the relapsed setting.⁵ 

In the report by Bride et al, T-ALL samples from patients enrolled in the COG AALL1231 study were noted to have consistent CD38 expression at the time of diagnosis and after completion of 1 month of induction chemotherapy. Moreover, CD38 was present at the time of T-ALL relapse. Next, the authors investigated the role of targeting CD38 in a PDX model of T-ALL using daratumumab, a monoclonal IgG1κ antibody against CD38 that is FDA approved for treatment of relapsed/refractory multiple myeloma (MM).⁶  Interestingly, treatment with daratumumab at high tumor burden (defined as 1% circulating cells) was associated with severe toxicity in many non–ETP-ALL-PDX models, presumably from overwhelming tumor lysis. This toxicity could be abrogated by initiating treatment at a lower disease volume with excellent efficacy in most of their non–ETP-PDX models. Between the 2 conditions, high tumor volume or low tumor volume, they were able to show significant activity of daratumumab in 14 of 15 PDX models. The only PDX leukemia that failed to respond to daratumumab treatment had low expression of the CD38 target molecule.

This study is compelling because it provides strong evidence that daratumumab should have clinical efficacy in T-ALL, including the ETP-ALL subtype. This finding is notable because the ETP-ALL subtype was initially identified as a high-risk subtype of T-ALL with poor outcomes and an immunophenotype that includes 1 or more myeloid or stem cell markers.³  Although some recent trials have reported intermediate-risk outcomes on current treatment protocols for children, analysis of ETP-ALL treatment in adults has shown it to have inferior prognosis to non–ETP-ALL.^7,8  The prospect of a new immunotherapy that is active in both ETP-ALL and non–ETP-ALL is promising for improving therapy in this difficult-to-treat subset of ALL.

CD38 is a 45-kDa type II transmembrane protein expressed on a variety of lymphoid and myeloid cells in addition to nonhematopoietic cells. CD38 is thought to function as both a receptor and an ectoenzyme, the latter function contributing to nucleotide metabolism by degrading extracellular nicotinamide adenine dinucleotide (NAD⁺) and nicotinamide adenine dinucleotide phosphate (NADP).⁶  Because of the high expression of CD38 on MM cells, anti-CD38 antibodies were pursued as an immunotherapy for MM. This has led to the development of several anti-CD38 antibodies, including daratumumab, isatuximab, and MOR202. As we have noted before, daratumumab currently is approved for treatment of relapsed/refractory MM. It is well tolerated with the most common adverse effect being infusion reactions, which tend to improve after repeated dosing. In addition, daratumumab was found to bind to CD38 on red blood cells, leading to a panreactive indirect antiglobulin test. Clinicians and blood bank personnel need to consider this interaction when transfusing patients who have received daratumumab treatment.

During preclinical development, daratumumab was specifically selected for its ability to mediate complement-dependent cytotoxicity (CDC).⁹  It is has also been shown to kill target cells via antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and FCγR-mediated cross-linking–induced apoptosis.⁶  Anti-CD38 antibodies, including daratumumab, can also inhibit the enzymatic function of the ectodomain, which might also contribute to their efficacy. The nonobese diabetic/severe combined immunodeficiency (NOD/SCID/Il2rg^tm1wjl/SzJ) mice that were used for the PDX model are notable for their severe immunodeficiency including lack of complement; absence of T cells, B cells, and natural killer cells; and defective macrophages.¹⁰  As the authors noted, the efficacy of daratumumab observed in their PDX model was without the ability to engage in CDC or ADCC. Future studies investigating the relative contribution of ADCP, FCγR-mediated cross-linking–induced apoptosis, and enzymatic inhibition will be important to optimize targeting of CD38 in T-ALL. Moreover, it will be interesting to see if the clinical efficacy of daratumumab is greater when it is able to engage in its full range of effector functions.

Establishing CD38 as a bona fide immunotherapy target in T-ALL should finally bring targeted therapy to the treatment of this disease. As noted before, further work on how to best leverage this target should lead to optimized antibody selection. In addition, CD38 can be further developed as a target for novel antibody drug conjugates and CD38-directed CAR T-cell therapy for T-ALL. Clinical trials testing the efficacy of anti-CD38 antibodies in T-ALL are currently being planned, and we eagerly await the results.