Advances in the treatment of ALL ( acute lymphoblastic leukemia)

Posted on in Brilliant Science, General

Current Immunotherapy Targets in Adult Relapsed/Refractory ALL (acute lymphoblastic leukemia)

The 3 main categories of immunotherapies used in ALL: ADCs, BiTE constructs, and CAR T-cells.[14] This activity will predominantly focus on the therapies that leverage the immune system to fight ALL—the BiTE constructs and CAR T-cells—but ADCs are important in this setting as well.

ADC- antibody- drug combinations
Inotuzumab ozogamicin is a CD22-directed ADC that was FDA approved in 2017 for treatment of adults with relapsed/refractory B-cell precursor ALL.[15] It comprises an anti-CD22 antibody bound to the cytotoxic agent calicheamicin.[8] Once the antibody binds to the cell-surface glycoprotein CD22, it is internalized and the calicheamicin releases and then binds to DNA, causing DNA damage and cell death.

This mechanism of targeted cell killing is quite effective. In the phase III INO-VATE ALL trial that led to the FDA approval, the CR rate with inotuzumab ozogamicin was dramatically and significantly higher vs standard intensive chemotherapy in adults with relapsed/refractory B-cell ALL (80.7% vs 29.4%, respectively; < .001). The safety profile of inotuzumab ozogamicin is notable for hepatotoxicity, particularly veno-occlusive liver disease, which is more likely to occur in a subset of patients. INO-VATE reported that 11% of inotuzumab ozogamicin–treated patients developed veno-occlusive disease, with most of these cases being grade ≥ 3. Most instances of veno-occlusive disease occurred among those who underwent transplantation after the study, and an analysis identified use of a dual-alkylator vs a single-alkylator conditioning regimen as a significant risk factor for veno-occlusive disease (= .04).

BiTE Constructs  (bispecific T-cell engagers -BiTE)

One advantage of a BiTE construct is that it is an “off the shelf” therapy—it does not need additional development or manufacturing, and can be promptly started in patients with relapsed/refractory ALL. As a targeted antibody construct, it is associated with less nonspecific cytotoxicity compared to globally immune-activating therapies. It acts independent of major histocompatibility complex or T-cell antigen specificity. Consistent with our focus here, BiTE constructs reactivate T-cells within the tumor microenvironment and leverage the immune system to eliminate malignant cells. Finally, the short half‑life of BiTE constructs enables rapid discontinuation if AEs should occur, especially serious events such as CRS or neurologic toxicities.

Both the BiTE construct blinatumomab and CAR T-cell therapies harness the power of the immune system, specifically T-cells, in attacking malignant B-cells. The common mechanism with these therapies is a T-cell–mediated cytotoxicity that eliminates malignant B-cells in ALL. Each therapy takes a different approach toward this common goal. In the case of blinatumomab, this agent acts by drawing ALL cells to cytotoxic T-cells by targeting both CD19 on malignant B-cells and CD3 on T-cells.[16] This forced proximity leads to T-cell activation, proliferation, and T-cell–mediated lysis of the malignant B-cell.

CAR T-Cell Therapies

CAR T-cell therapies, which are a very promising and exciting class of anticancer agents. As discussed earlier, these are autologous T-cells engineered to express a chimeric antigen receptor; for ALL, the CAR can target CD19 on the malignant B-cell surface and activate the engineered T-cell through its intracellular domain.[25-27] The process of generating CAR T-cells begins by performing leukapheresis to collect T-cells from the patient. Next, the CAR gene is inserted into a retroviral vector for transducing the T-cells. The CAR T-cells are then expanded ex vivo. As the CAR T-cells are being developed, the patient may undergo salvage chemotherapy. When the CAR T-cells are ready, patients first receive conditioning chemotherapy, such as fludarabine or cyclophosphamide. The CAR T-cells are then reinfused into the patient with B-cell ALL, and the patient is monitored for toxicity and clinical response. A recent analysis observed a median duration of 23 days (range: 21-37) from receipt of leukapheresis cells at the manufacturing facility to return of the manufactured tisagenlecleucel to the clinical site.[28]

A similar goal exists with CAR T-cell therapies, which are in use and under development for multiple hematologic malignancies. In the setting of B-cell ALL, CAR T-cell therapies, such as tisagenlecleucel, are designed to target CD19-positive B-cells.[17] Autologous T-cells collected from the patient are genetically modified to express a CD19‑targeted CAR. These transduced T-cells are then reinfused into the patient, where they can expand and persist as active immunologic agents. Once in the patient, the CAR T-cells bind to CD19 on the surface of malignant B-cells, leading to CAR T-cell activation, expansion, and elimination of the malignant B-cell.