Novel Therapeutics Targeting CD19 and CD22 in Adult Acute Lymphoblastic Leukemia

Jessica K. Altman, MD

Leukemia

Outcomes in adult acute lymphoblastic leukemia (ALL) remain poor, with long-term disease-free survival (DFS) rates of 30% to 40%.¹ Salvage chemotherapy regimens demonstrate limited success in inducing and maintaining a second remission, and consequently overall survival (OS) at 5 years after relapse is as low as 7%.² Therefore, novel agents with alternative mechanisms of action are essential for improving outcomes in both newly diagnosed and relapsed/refractory disease. Because the cell surface antigen CD19 is expressed on up to 100% of B-lineage ALL (B-ALL) blast cells and CD22 is expressed on up to 90% of B-ALL blasts, they have become highly investigated targets for immunotherapies.³ This review will focus on monoclonal antibodies, antibody-drug conjugates, bispecific T-cell–engaging antibodies, and chimeric antigen receptors that specifically target CD19 and/or CD22.

CD19

CD19 expression on the B-cell surface continues from the time of B-lineage commitment during hematopoietic stem cell differentiation until it is downregulated during terminal differentiation into plasma cells. CD19 expression is maintained in B-lineage cells that have undergone neoplastic transformation and has a high density of expression, making it an ideal target for immunotherapies.^3,4

CD19 Monoclonal Antibody (Table)

MEDI-551 is a humanized monoclonal anti-CD19 antibody that is known to have antileukemic activity both in vitro and in clinical trials via antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis in chronic lymphocytic leukemia.^5,6 In vitro studies in B-ALL cell lines demonstrate interaction between anti-CD19–bound target leukemia cells and effector cells, resulting in recruitment of natural killer (NK) cells and macrophages to induce NK-mediated killing and macrophage phagocytosis of blasts. In a xenograft ALL model, treatment with MEDI-551 resulted in decreased disease burden and prolonged survival.⁷ Therefore, this drug should be investigated further in early-phase clinical trials in B-ALL.

CD19 Antibody-Drug Conjugate (Table)

SAR3419 is a humanized monoclonal IgG1 antibody attached to the tubulin inhibitor maytansinoid DM4 by the cleavable linker N-succinimidyl-4-butyrate.⁸ DM4 is similar to vinca alkaloids but with over 100-fold higher potency.⁸ After SAR3419 binds to the CD19 antigen on the B-cell surface, it is endocytosed and routed to the lysosomes and cytoplasm for degradation and release of the DM4 toxin.⁸

Early-phase studies of SAR3419 in relapsed/refractory B-cell non-Hodgkin lymphomas (NHLs) demonstrated safety and efficacy with weekly dosing.⁹ This prompted preclinical investigation in ALL. In vivo SAR3419 delayed tumor progression and produced objective responses in ALL xenograft models, including those with chemoresistant disease. In untreated ALL xenograft models, SAR3419 enhanced the antileukemia effects of vincristine, dexamethasone, and asparaginase induction therapy. Further, when administered after attainment of remission, SAR3419 prevented disease recurrence.¹⁰

CD19 Bispecific T-Cell–Engaging Antibody (Table)

Blinatumomab is a bispecific T-cell–engaging antibody that combines 2 single-chain antibodies directed against CD19 and CD3.¹¹ While targeting the CD19-
expressing B cells, it is able to recruit CD3-expressing cytotoxic T cells, thus directing T cells to malignant B cells for perforin-mediated cell death. Binding both CD19 and CD3 is required for T-cell activation and prevents uncontrolled cell lysis.¹² The first reports of blinatumomab safety and activity were in relapsed NHLs with a dose of 15 ?g/m²/24 hours IV administered continuously for 4 weeks, resulting in elimination of tumor cells from the bone marrow.¹² The same dose and schedule was therefore used in patients who never achieved minimal residual disease (MRD) negativity or molecularly relapsed B-ALL. MRD positivity was defined as a quantifiable MRD load of ?1Ă—10-4 by quantitative reverse transcriptase-polymerase chain reaction. Eighty percent of patients became MRD negative, including 57% of patients who were molecularly refractory to prior chemotherapy. Lymphopenia was the most common toxicity grade ?3. Additional common adverse events (AEs) included pyrexia, chills, decreased blood immunoglobulin, and hypokalemia.¹³ Follow-up of this study after a median of 33 months was significant for a hematologic relapse-free survival (RFS) of 61% for the entire evaluable study cohort of 20 patients. The hematologic RFS of the 9 patients who received an allogeneic hematopoietic stem cell transplant (HSCT) after blinatumomab treatment was 65% after a median follow-up of 33 months. Notably, 67% of Philadelphia chromosome (Ph)-negative MRD responders with no further therapy after blinatumomab remained in hematologic and molecular remission after a median follow-up of 30 months, demonstrating similar rates of long-term DFS in patients who did or did not undergo HSCT. This is one of the first novel agents showing the ability to induce a long-lasting complete remission (CR) in ALL refractory to chemotherapy, suggesting it may be beneficial for the frontline treatment of ALL.¹⁴ The recently opened United States Intergroup Trial, ECOG 1910, is comparing blinatumomab plus chemotherapy with chemotherapy alone in adults with newly diagnosed B-ALL (NCT02003222).

Analysis of serum samples from the clinical trial for MRD-positive patients confirmed on-target activity of blinatumomab by depleting CD19-expressing B cells both during and between treatment cycles. Cytokine levels, including interleukin (IL)-2, IL-6, IL-10, interferon-gamma, and tumor necrosis factor-alpha, increased early in the first cycle with a high interpatient variability and were no longer detected after beginning cycle 2, suggesting that cytokine-release syndrome (CRS) may be most prevalent with the first cycle of treatment. While peripheral T-cell counts initially dropped with treatment, likely due to rapid cell redistribution, they recovered within several days and expanded above baseline counts. Additionally, a large proportion of recovering T cells demonstrated increased expression of the activation marker CD69. Patients who did not respond to treatment also had evidence of T-cell expansion and activation. Further, the degree of CD19-positive B-cell disease burden in the bone marrow did not correlate with response. This may be due to molecular abnormalities or mechanisms of resistance to blinatumomab in the leukemia cells that have not yet been identified.¹⁵

The same group investigated blinatumomab in 36 patients with relapsed/refractory B-ALL in a phase 1 dose-escalation trial. Seventy-two percent of patients achieved a CR or CR with incomplete blood count recovery (CRi), and 92% of these also achieved a molecular response. Ninety-five percent of patients in first relapse responded, whereas only 40% of the remaining patients achieved a CR. Thirteen of 26 responders went on to transplant. Eight of the remaining 13 responders relapsed. The median OS for patients who achieved a CR was 14.1 months. CRS, characterized by pyrexia, rigors, and hypotension, as well as central nervous system (CNS) events, was the most common clinically significant AE. The doses of 5 ?g/m²/day in week 1 and 15 ?g/m²/day for the remaining treatment of a 28-day cycle were selected for further investigation in the extension cohort. The lower starting dose likely reduces the risk of CRS associated with higher disease burden.¹⁶ Given that blinatumomab was generally tolerable, produced high complete hematologic and molecular remission rates, and improved survival in this and a larger multicenter phase 2 study in relapsed/refractory ALL, the drug was recently approved by the FDA in December of 2014.¹⁷



CD22

CD22 is a B-cell–specific cell surface glycoprotein of the immunoglobulin superfamily thought to be involved in B-cell survival, activation, proliferation, migration, and interaction with T cells and antigen-presenting cells through both ligand-dependent and -independent mechanisms.¹⁸ CD22 is expressed on up to 93% of B-lymphoblasts in ALL. Because B cells internalize CD22 after binding the ligand or antibody, it provides a convenient means for cytotoxic drug delivery by antibody-drug conjugates.³ Clinical data showed a positive correlation between CD22 expression and OS, suggesting it may play an important role in leukemogenesis that can be effectively treated.¹⁹

CD22 Monoclonal Antibody (Table)

Epratuzumab is a humanized anti-CD22 monoclonal antibody that modulates B-cell activation and signaling and induces cell lysis by ADCC.20 A pediatric relapsed/refractory ALL pilot study of epratuzumab, followed by epratuzumab with chemotherapy, demonstrated that it was tolerable as a single agent and when combined with chemotherapy. Grade 1 or 2 infusion reactions were observed in 10 of 15 patients with the initial epratuzumab infusion. Two patients experienced dose-limiting toxicities (DLTs), including grade 4 seizure with epratuzumab and grade 3 transaminase elevation with epratuzumab in combination with chemotherapy. After single-agent epratuzumab, 1 patient (7%) achieved a partial response. Nine patients (60%) achieved a CR after chemoimmunotherapy, 7 of whom were MRD negative. In all but 1 patient, surface CD22 was not detected by flow cytometry on peripheral blood leukemic blasts within 24 hours of drug administration, indicating effective targeting of leukemic cells by epratuzumab.²¹ Based on these results, the regimen was evaluated further in a pediatric phase 2 trial of chemotherapy and epratuzumab concurrently. Sixty-six percent of 108 patients evaluable for response achieved a CR, and among 62 of these patients with available MRD data, 42% were MRD negative, which was significantly higher than the historical control of chemotherapy alone. Further follow-up data will be required to evaluate the impact this has on duration of response (DOR) and OS.²²

In adult patients, epratzumab was combined with cytarabine and clofarabine in relapsed/refractory B-ALL in a phase 2 trial. Seventeen percent of patients experienced grade 4 nonhematologic toxicities, including hypercalcemia, elevated transaminases, febrile neutropenia, acute kidney injury, hepatic failure, pneumonia, hypoxia, and respiratory failure. Among 29 evaluable patients, the response rate was 45%, including 8 patients with a CR and 5 with a CRi. Only 5 of these patients had MRD assessments, of which 1 achieved a significant MRD response.²³ Compared with a historical control of clofarabine and cytarabine (SWOG S0530), the response rate and MRD negativity suggest an added benefit to chemoimmunotherapy with epratuzumab; however, as with the pediatric studies, further studies are necessary to determine the effect on DOR and OS.²⁴

CD22 Antibody-Drug Conjugate (Table)

BL22

BL22 is an antibody-drug conjugate made up of the variable domains of the anti-CD22 monoclonal antibody RFB4 fused to a fragment of Pseudomonas aeruginosa exotoxin A. BL22 caused cell death in vitro in ALL blasts and prolonged leukemia-free survival in ALL xenograft models in vivo. In a phase 1 clinical trial of BL22 in pediatric relapsed/refractory ALL, grade 1-2 liver function test abnormalities were the most common AEs. Two patients experienced grade 4 ALT elevation; however, this was reversible. Whereas no patients met remission criteria, 16 of 23 subjects (70%) had peripheral blast reduction, bone marrow blast reduction, or recovery of blood counts.²⁵

Moxetumomab Pasudotox

Given limited efficacy, the latter trial was closed and high-affinity BL22 (also known as HA22, CAT-8015, or moxetumomab pasudotox [MP]), a BL22 construct with 14-fold higher antibody affinity for CD22, was investigated further. In vitro data for MP demonstrated cytotoxic activity in blasts from ALL patients with newly diagnosed and relapsed disease.²⁶ The level of CD22 surface expression did not correlate with MP cytotoxicity in vitro. However, the binding and internalization of MP correlated with response. Additionally, cleavage of MP to an active toxin intracellularly correlated with cellular uptake and inhibition of protein synthesis. This suggests that resistance to MP may be related to heterogeneity of blasts binding and internalizing the drug. Further studies will need to investigate the role of MP cleavage and trafficking within the cell to further elucidate mechanisms of action and resistance.²⁷

In the phase 1 trial of MP in relapsed/refractory pediatric ALL, 3 of 12 patients (25%) achieved a CR by morphology and flow cytometry, 5 (42%) had blood count improvement or blast reduction, and 3 (25%) had stable disease.²⁸ Therefore, MP is currently under investigation in children and young adults with relapsed/refractory CD22-positive ALL or NHL, as well as adults with relapsed/refractory ALL (NCT00659425, NCT01891981).

Inotuzumab Ozogamicin

Inotuzumab ozogamicin (IO) is a humanized anti- CD22 antibody conjugated at the Fc portion to calicheamicin, a cytotoxic agent that cleaves double-stranded DNA. In vitro, IO inhibited ALL cell growth, and in vivo, it resulted in tumor regression and cure in tumor-bearing mice.²⁹ Another in vitro study with pediatric B-ALL cells demonstrated that CD22 expression was essential for uptake of IO. However, complete and prolonged CD22 saturation and inhibition were not required for apoptosis; therefore, patients may benefit from multiple low IO dosages.³⁰

Based on safety and efficacy in lymphoma, a phase 2 trial of IO 1.8 mg/m² IV every 3 to 4 weeks was conducted in 49 children and adults with relapsed/refractory ALL. CD22 was expressed on more than 50% of blasts in all patients. Eighteen percent of patients achieved a CR, and 39% a CRi; however, the median DOR was limited to 6.3 months. Although a relatively high number of patients (33%) went on to transplant, this did not provide additional survival benefit, with a median OS in all responders of 7.9 months versus a median OS in HSCT patients of 5.2 months. In addition to high rates of fever (59%) associated with drug infusion, increased liver enzymes occurred in 28 patients (57%), and 14 patients (28%) experienced increases in bilirubin concentrations.³¹ An additional 34 patients were treated with IO weekly, which was equally effective (CR 53%, median OS 6.3 months) and less hepatotoxic than the single-dose schedule. In patients who went on to HSCT, veno-occlusive disease was observed in 5 of 22 patients (23%) with single-dose IO and in 1 of 9 patients (11%) with weekly dose IO.³²

Another phase 2 trial evaluated a similar IO weekly dosing regimen and found the most frequent treatment-related AEs were cytopenias and transaminitis. One DLT of grade 4 lipase elevation occurred. The overall response rate (ORR) was impressive at 82% (9 of 11 evaluable patients), including 36% with CR and 45% with CRi. Six of 9 responders (67%) also achieved negative MRD.³³ This confirmed promising response rates with IO as a single agent in the adult relapsed/refractory B-ALL population. Further follow-up data are expected from these trials regarding DOR and OS.

Preliminary results from a phase 1/2 trial investigating IO combined with low-dose chemotherapy (cyclophosphamide, vincristine, cytarabine, methotrexate, dexamethasone, and rituximab) in newly diagnosed elderly (>60 years of age) ALL patients showed activity with IO in the frontline setting. Of 14 evaluable patients, 12 achieved CR and 1 CRi (ORR 93%), as well as molecular remissions. After a median follow-up of 10.8 months, 1-year DFS and OS were 83% and 93%, respectively. Six patients discontinued induction chemotherapy due to thrombocytopenia, but no DLTs occurred, suggesting that this may be a promising regimen in elderly patients.³⁴ Trials are currently ongoing to evaluate the role of IO in the context of allogeneic HSCT, as well as efficacy and survival benefit in a randomized phase 3 trial comparing IO with salvage chemotherapy in patients with relapsed/refractory ALL (NCT01664910, NCT01564784).

Combination Antibody-Drug Conjugate (Table)

Combotox is a novel agent that combines 2 antibody-drug conjugates, consisting of one murine IgG monoclonal antibody targeting CD19 (HD37) and another targeting CD22 (RFB4) conjugated to the toxin deglycosylated ricin A chain (dgRTA) in a 1:1 ratio. HD37-dgRTA, RFB4-dgRTA, and Combotox all resulted in cytotoxicity in a dose-dependent fashion in ALL cell lines. When tested in pediatric B-ALL blast samples, the individual immunotoxins were effective; however, Combotox caused the highest rate of cell death compared with either immunotoxin alone.³⁵ Similar findings were noted in vivo, particularly in limited-stage disease, and resulted in decreased disease burden and improved survival.³⁶

A phase 1 clinical trial with Combotox in 17 patients with relapsed/refractory pediatric pre–B-ALL reported an 18% CR rate; however, 35% had a >95% decrease in their peripheral blood blast counts, and 1 patient had a 75% decrease in peripheral blood blast count. Severe toxicities possibly related to Combotox included grade 3 pancreatitis, grade 3 anaphylaxis, and grade 4 graft-versus-host disease (GVHD), each in 1 patient.³⁷ A subsequent phase 1 trial in 17 adult patients with relapsed/refractory B-ALL identified vascular leak syndrome as the DLT. Two other patients experienced grade 3 transaminitis that was reversible. One patient had 80% involvement of the bone marrow with blasts, which decreased to 10% after Combotox treatment, suggesting a partial response, and subsequently underwent allogeneic HSCT. All patients with peripheral blood blasts demonstrated decreased blast counts after Combotox.³⁸ Whereas Combotox reduced the leukemic disease burden in all patients, it may require more frequent or extended treatments to achieve a higher degree of response. In particular, blasts increased quickly after completing the final Combotox dose, suggesting continuous dosing may be beneficial.

In a xenograft B-ALL model, a survival benefit was seen in mice treated with Combotox and cytarabine together, in particular when administered sequentially after cytarabine, reflective of synergistic activity.³⁹ Based on these findings, cytarabine and Combotox are currently under investigation in a phase 1 trial in adults with relapsed/refractory ALL (NCT01408160).

Chimeric Antigen Receptor T Cells (Table)

Chimeric antigen receptors (CARs) are composed of antibody-binding domains of single-chain variable fragments linked to T-cell–stimulating moieties, most commonly CD3-zeta. The chimeric receptor CTL019 binds CD19 on malignant B cells and leads to tyrosine kinase–mediated activation of the T cell through the CD3-zeta chain portion of the chimeric receptor and costimulatory activity of normal CD137. In chronic lymphocytic leukemia (CLL), CAR T cells expanded >1000-fold in vivo, trafficked to bone marrow, continued to be expressed at high levels for at least 6 months, and persisted as memory CAR T cells. Common AEs, but also evidence for on-target toxicity, included B-cell aplasia, decreased numbers of plasma cells, and hypo­gammaglobulinemia.^40,41

Subsequently, 2 children with relapsed/refractory B-ALL received infusions of CTL019 CAR T cells. One patient had chemotherapy-refractory disease, and the other patient relapsed after allogeneic cord blood transplant and did not respond to blinatumomab. Similar to the CLL experience, the CAR T cells expanded >1000-fold in vivo and were identified in the bone marrow as well as cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. This migration of CAR T cells into the CSF suggests a potential prophylactic CNS therapy for ALL. Both patients developed CRS and B-cell aplasia. CRS management with etanercept and tocilizumab to inhibit the cytokines did not impede expansion of CAR T cells or antileukemic efficacy. CR was observed in both patients by morphology and MRD negativity. CR was ongoing in the first patient 11 months after treatment. The other patient relapsed, with CD19-negative blast cells 2 months after treatment.⁴²

Longer follow-up data from pilot studies by these investigators, including 16 pediatric and 4 adult patients with relapsed/refractory ALL, showed a CR rate of 82% (14 of 17 evaluable patients), including 1 patient with CD19-positive T-cell ALL. The targeted T-cell dose in adults was 5Ă—109 cells divided over 3 days. All responding patients experienced CRS, which correlated with peak T-cell expansion. Eleven patients received CTL019 cells after allogeneic stem cell transplant with T cells of donor origin; however, no GVHD occurred. B-cell aplasia continued as long as CTL019 cells persisted, up to 15 months in some patients. Patients were treated with IV immunoglobulin, and no severe infectious complications were reported.⁴³

Another group treated 5 relapsed adult B-ALL patients with morphologic or MRD-positive disease and no prior HSCT with a dose of 3Ă—106 autologous T cells expressing a CD19-specific CD28/CD3-zeta second-generation dual-signaling CAR. Three patients remain in CR post HSCT; however, 1 died of a suspected pulmonary embolism. The 1 patient who was ineligible for further therapy relapsed with CD19-positive blasts 90 days after treatment in the setting of steroid therapy for cytokine-mediated toxicities, which may have limited CAR-modified T-cell persistence. Similar to the other studies, patients experienced CRS, worst in patients with the greatest tumor burden, which was also associated with the largest number of detectable CAR T cells. Whereas initial expansion of CAR T cells was observed in all patients, recovery of normal B-cell clones was also seen, consistent with waning persistence of CAR-modified T cells and, importantly, recovery of normal B-cell lymphopoiesis.⁴⁴

Longer follow-up of this study showed results for an additional 8 patients enrolled (n=13). Five of 7 patients with morphologic disease relapse (>5% to 70% blasts in bone marrow) at the time of CAR T-cell infusion achieved a molecular remission with MRD negativity. Five of 6 patients with MRD at the time of CAR T-cell infusion became MRD negative. Molecular remission was observed as early as 7 to 14 days after T-cell infusion. Additionally, among these patients 3 were Ph-positive B-ALL, demonstrating activity in ALL with the worst prognosis.⁴⁵

In another study of anti–CD19-CD28/CD3-zeta CAR T cells in pediatric relapsed/refractory B-ALL, 5 of 7 patients (71%) achieved a CR, including 3 who became MRD negative. One patient with CNS involvement cleared all blasts from the CSF without further intrathecal chemotherapy after receiving CAR T cells. At the time of day 28 restaging, 4 of 5 responding patients had detectable CD19-positive hematogones, suggesting that T-cell expansion and antileukemia effects can be maintained without chronic B-cell aplasia. GVHD was not seen in patients with prior HSCT who received donor-derived T cells.⁴⁶ These studies showed that CAR T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells and may prolong remission and survival via bridge to transplant or repeat infusion and maintenance therapy.

Conclusion

Several CD19 and CD22 antigen-targeted immunotherapies show great potential in B-ALL. The ability of these agents to induce molecular remissions in relapsed and refractory disease has the promise of improving survival outcomes in ALL. As well, this implies that there may be benefit to utilizing these agents in induction regimens for newly diagnosed B-ALL for greater depth of response to prevent relapse. Future trials will need to address how to effectively combine these agents with standard chemotherapy and other novel drugs as our understanding of the disease biology improves.

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