Detonating T-ALL

In this issue of Blood, Tran Quang et al show treatment with anti-CD3 antibodies produces potent antileukemic effects in mouse xenograft models of disseminated T-cell acute lymphoblastic leukemia (T-ALL).¹  Using several high-tumor-burden patient-derived xenograft (PDX) models of T-ALL, the authors demonstrate that 5 daily injections of anti-CD3 antibodies induced temporary regression of leukemia and prolonged mouse survival. Combining the antibody injections with vincristine and dexamethasone further enhanced these effects, resulting in complete eradication of established T-ALL in most animals. These results suggest anti-CD3 antibodies can be explored as a treatment of patients with sCD3⁺ T-ALL.

CD3 subunits are expressed on the cell surface primarily in medullary (mature) T-ALL, which comprises about half of all pediatric cases and ∼20% of cases in adults. These leukemic cells resemble mature thymocytes with partially or fully recombined T-cell receptor (TCR) chains that normally undergo positive and negative selection in the thymus. Negative selection occurs when a TCR binds to self-peptide–major histocompatibility complexes with exceedingly high affinity, triggering an apoptosis program that eliminates autoreactive T cells. Previously, the authors demonstrated the ability of a murine anti-CD3 antibody OKT3 (muromonab) to induce a similar TCR signaling in mature T-ALL blasts, directly activating the apoptotic program without utilizing FcR- and complement-dependent cytotoxicity mechanisms.²  In the current study, Tran Quang and colleagues showed teplizumab and foralumab, modified anti-CD3 antibodies with established clinical safety profile, promote robust antitumor activity in T-ALL PDX models by utilizing the mechanism described above (see figure).

Teplizumab is humanized, and foralumab is a fully human CD3ε-specific antibody; both harbor point mutations in the C_H2 Fc domain that reduce binding to Fc receptors and complement.³  Thus, these antibodies are less likely to induce cytokine release and the toxicities associated with the use of muromonab in the clinic. Both CD3-specific antibodies can suppress unwanted pathogenic autoimmune and alloimmune T-cell responses by promoting TCR signaling-induced anergy and apoptosis in pathogenic T cells and by stimulating the expansion of regulatory T cells.^3,4  Teplizumab and foralumab have shown acceptable safety profiles at lower doses in patients with autoimmune diseases (type 1 diabetes and Crohn disease).^5,6  Following corticosteroid premedication, teplizumab was also tolerated at higher doses to prevent T-cell–mediated allograft rejection in patients with renal transplant.⁷  Whether the antileukemic activity of teplizumab and/or foralumab observed in the current report will be retained at clinically tolerated doses in T-ALL patients remains to be evaluated in phase 1/2 studies.

The antileukemic effect of induced TCR/CD3 signaling in T-ALL comes in stark contrast to mature T-cell neoplasms, such as peripheral T-cell lymphoma, where TCR signaling is thought to promote survival and oncogenesis. Therefore, the selective pressure of an anti-CD3 antibody may favor outgrowth of leukemic clones with negative or dim expression of CD3. Indeed, the authors detected such a selection of CD3-negative clones in some T-ALL PDX treated with anti-CD3 antibodies.^1,2  Although antigen escape may limit the efficacy of the CD3-specific monotherapy, the authors demonstrated that a combinatorial approach with chemotherapy further suppresses propagation of resistant leukemic clones.¹  Future studies should explore the efficacy of combining these antibodies with other therapeutic agents such as immunotherapies. Moreover, eliminating CD3⁺ T-ALL blasts may reduce tumor burden significantly enough to enable patients to proceed with potentially curative allogeneic stem cell transplant.

Unlike B-ALL, where targeting CD19, CD20, or CD22 with monoclonal antibodies and bispecific engagers can produce significant clinical benefit, options for immunotherapy of refractory and relapsed T-ALL remain very scarce, contributing to poor prognosis.⁸  The aggressive nature and rapid progression of this disease require agents that are fast and effective. Recent studies have demonstrated the efficacy of a cytotoxic anti-CD38 antibody daratumumab in PDX-based preclinical models of T-ALL⁹ ; a phase 2 clinical trial in pediatric and young adult patients with lymphoblastic leukemia is currently underway (#NCT03384654). In addition, chimeric antigen receptor T-cell–based therapies targeting CD5 and CD7 are being evaluated in phase 1 studies in patients with T-ALL.¹⁰  This work by Tran Quang and colleagues reveals CD3 as a very promising target for the immunotherapy of medullary T-ALL, a much-needed potential therapeutic option for patients with refractory or relapsed disease.