T-cell Lymphoblastic Leukemia: What Are the Prospects for Novel Immunotherapy?

The Case

A 22-year-old woman presented to an academic medical center with a four-week history of night sweats and tender progressive right cervical lymphadenopathy. A computed tomography (CT) scan of the neck revealed right cervical and supraclavicular lymphadenopathy (1.7 × 1.7 cm) with central necrosis. A soft tissue density (2.8 cm) in the anterior mediastinum was compressing the superior vena cava. A CT scan of the chest, abdomen, and pelvis revealed no enlarged lymph nodes and a normal-sized spleen. The complete blood count revealed a white blood cell count of 7.7 × 10⁹/L; hemoglobin, 10.4 g/dL; hematocrit, 29 percent; platelets, 88 × 10⁹/L; and absolute neutrophil count, 3.5 × 10⁹/L. There were 20 percent blasts in the white cell differential count.

A cell suspension from a marrow aspirate was examined by flow cytometry, and the blast population expressed CD7, CD34, CD56, cytoplasmic CD3, human leukocyte antigen–DR, and partial CD15. The blast population was negative for CD1a, CD2, CD4, CD8, CD5 (dim), CD10, CD20, CD22, CD117, CD64, CD14, CD79a, and TdT. Chromosome analysis revealed a near triploid composite karyotype with 77 to 81 chromosomes. The molecular profile revealed no mutations in NOTCH1, FLT3 or IDH1, or IDH2. The spinal fluid did not contain leukemia cells. The lactate dehydrogenase was 327 U/L (normal range, 118-225 U/L). Her diagnosis was early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). She was started on a standard four-drug induction regimen that included vincristine, dexamethasone, daunorubicin, and pegaspargase, including central nervous system prophylaxis.

Minimal residual disease (MRD) assessment was performed by multiparameter flow cytometry on day 29 of induction therapy and revealed a value greater than 0.1 percent. The patient continued on a pediatric consolidation regimen of augmented Berlin-Frankfurt-Munster (aBFM) protocols with the addition of nelarabine. Following completion of the consolidation course, MRD assessment was repeated and showed detectable disease (>0.1%). Given the high risk of relapse based on the end-of-consolidation MRD assessment, the patient was referred for allogeneic hematopoietic stem cell transplant (HSCT). As the patient was preparing for allogeneic HSCT, a marrow biopsy was performed as part of the pretransplant evaluation, and she was found to have 35 percent blasts in the aspirate specimen, consistent with relapsed T-cell ALL.

Current State of T-ALL Treatment/Challenges in Diagnosis and Management

T-lineage ALL (T-ALL) is curable for most children and adolescents and young adults (AYAs; defined as those aged 15-39 years), with contemporary frontline chemotherapy regimens.^1,2  For children and AYAs, the pediatric-inspired, modified aBFM backbone including nelarabine has become the standard chemotherapy regimen in the United States.¹  Despite the best initial chemotherapy, approximately 30 percent of children and adult patients will have MRD following induction and consolidation, a known risk factor for relapse,³  and approximately 15 percent of children and 25 percent of AYAs will have refractory disease or will relapse after an initial response.^1,2  For adults 40 years and older, however, no comparably effective initial standard therapy exists. Because older adults cannot tolerate the use of high-intensity regimens inspired by pediatric studies, either dose-modified hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone),⁴  the regimen from the trial of the Medical Research Council in the UK and the Eastern Cooperative Oncology Group (E2993/UKALL12),⁵  or Cancer and Leukemia Group B protocols^6,7  are commonly chosen. For adults with T-ALL treated on the E2993/UKALL12 study, the five-year incidence of relapse after initial response was 42 percent.⁵  Relapsed T-ALL is rarely cured in children or adults, with the overall survival rate for children being less than 30 percent, and for adults, less than 10 percent.^5,8 

The major reason for the dismal prognosis after relapse is that current salvage therapies for T-ALL are ineffective for a majority of adults (60-70%) and too many children (30-40%), and no novel immunotherapy or targeted therapy has been established for patients with T-ALL. Unlike in B-lineage ALL (B-ALL), where immunotherapies targeted to CD19 or CD22 have significantly improved survival rates in relapsed disease, comparable therapies are not available or effective in T-ALL. Thus, for T-ALL, novel therapy is needed for 1) high-risk disease as defined by detectable MRD following induction and consolidation therapy, as described in the case report; 2) relapsed T-ALL, which has no effective salvage therapies; and 3) frontline treatment for older adults who cannot tolerate the intensity of pediatric regimens. This need has led to a burgeoning activity in the case of T-ALL to develop the same immunotherapies, including chimeric antigen receptor T-cell (CAR-T) platforms and monoclonal antibodies, as have been developed for B-ALL. This review will focus on these novel approaches and highlight immunotherapies currently in clinical trials. For the interested reader, several excellent reviews of T-ALL treatment and descriptions of genomic landscape have been published recently.^9-12 

Monoclonal Antibodies

CD38 is a type II-transmembrane glycoprotein found on the surface of lymphocytes, including T and B lymphocytes, plasma cells, and natural killer cells. Its functions include regulation of intracellular calcium and signal transduction in immune cells. The laboratory of Dr. David Teachey and other labs have characterized CD38 expression in T-ALL to determine whether CD38 would be an effective target in this disease.¹³  The Teachey laboratory uncovered that blasts from pediatric patients with T-ALL have robust cell surface CD38 expression at the time of diagnosis, and that CD38 expression is maintained following chemotherapy. Further, there was low CD38 expression on normal lymphoid and myeloid cells and nonhematopoietic organs, suggesting minimal “off target” toxicity. The lab expanded the work to test daratumumab, a human immunoglobulin G1k monoclonal antibody that binds CD38 and is approved for myeloma therapy, and to determine its efficacy in patient-derived xenograft models of T-ALL. Daratumumab was highly effective in their model. In support of this approach are clinical case reports of compassionate use of daratumumab in relapsed T-ALL that have demonstrated prolonged responses.¹⁴  Collectively, the results support the likelihood that CD38 is a good therapeutic target for T-ALL and may be particularly useful in the clinical setting of detectable MRD following cytotoxic chemotherapy, as CD38 expression seems to be preserved following exposure to chemotherapy. To this end, daratumumab is being tested in combination with cytotoxic chemotherapy in an international multicenter phase I/II trial (NCT03384654) for children and AYA patients (ages 1-30 years) with relapsed or refractory B-cell and T-cell ALL and lymphoblastic lymphoma. Another monoclonal antibody targeting CD38, isatuximab, has been developed and was being tested as a monotherapy in a phase II trial (NCT02999633) for relapsed or refractory T-ALL or T-lymphoblastic lymphoma; however, the trial was closed permanently due to an unsatisfactory risk-benefit ratio. It is thought that the kinetics of response to anti-CD38 monotherapy are relatively slow, which is insufficient in an aggressive leukemia such as T-ALL. Therefore, the better strategy in this disease seems to be combining the antibody with cytotoxic chemotherapy. Thus, a second trial is ongoing in Canada and Europe for pediatric patients with either relapsed ALL or acute myeloid leukemia — a phase II study of the antibody in combination with cytotoxic chemotherapy (NCT0386044).

CAR-T Therapy

There are several hurdles to developing CAR-T therapy for the treatment of T-lineage leukemia. The complexity of harvesting T cells for the creation of the CAR-T construct results from the need to collect adequate numbers of normal T-cells from the patient without contamination of malignant T-cells. An alternative approach would be the use of genetically modified CAR-Ts from healthy allogeneic donors, an approach that may result in life-threatening graft-versus-host disease (GVHD) when the allogeneic cells are infused into immunocompromised patients.

Additionally, the targeting of lineage-restricted antigens on malignant T cells could result in two important adverse consequences: 1) fratricide, which in this scientific context refers to the nonspecific killing of the CAR-T construct; and 2) prolonged T-cell aplasia. Because the most widely expressed tumor antigen targets for malignant T cells are also expressed on normal T cells, the engineered T-cells can result in CAR-T fratricide during manufacturing and therefore limit ex vivo expansion and therapeutic potency of the autologous cell product. Once fratricide is resolved, there remains the issue of prolonged T-cell aplasia. CAR-T cytotoxicity against normal lymphocytes and their early precursors will suppress overall T-cell function and induce temporary or prolonged immunodeficiency, clinically similar to that observed following HSCT. There is no easy, clinically useful treatment to help with prolonged T-cell aplasia. Only time or potentially curative HSCT (as allogeneic HSCT terminates the activity of CAR-Ts) restores normal hematopoiesis and ultimately replenishes T-cell populations. In contrast, the prolonged B-cell aplasia from targeting CD19 in B-cell malignancies can be treated with intravenous immunoglobulin. Lastly, there is a risk of genetically modifying circulating malignant T-lymphoblasts, which could facilitate a treatment-resistant tumor clone.¹⁵ 

Despite the technical and clinical challenges, several laboratories have developed CAR-T constructs, using strategies that address each of the technical and clinical hurdles described above, and early-phase clinical trials are underway (Table). Investigators at Baylor University have designed CAR-T constructs targeting CD5 and CD7 that eliminate fratricide, but these common T-lineage antigens will eliminate normal T-cell subsets and cause profound immunosuppression, so current trials are designed as a “bridge to transplant.”^16,17  In the United Kingdom, scientists have used TRBC1 as a target, which is expressed in approximately 35 percent of T-ALL cases. This approach was designed to spare large subsets of normal T-cells to reduce T-cell aplasia.¹⁸  In an alternative approach, scientists at Washington University in St. Louis have designed an “off-the-shelf” CAR-T construct, UCART7, which is resistant to fratricide, exhibits no alloreactivity or GVHD potential, and expands and persists, and efficiently eliminates CD7⁺ T-ALL in vivo.^19,20  The laboratory manipulations that were used to work around the obstacles are beyond the scope of this review, but are described in the references for the interested reader.