Immunotherapy in hematological malignancies at ASH 2019

Saturday 21st December 2019

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Research into immune therapies to treat hematological malignancies continues to grow with promising results in heavily pre-treated patients

A total of 118 abstracts on chimeric antigen receptor (CAR) T-cell therapies were presented at the  61st Annual American Society of Hematology (ASH) Conference in Orlando, with additional abstracts on novel immune cell therapies, highlighting that interest and research into immune therapies to treat hematological malignancies continues to grow. 

CAR T-cell therapies are synthetic constructs that, when expressed in T-cells, mimic T-cell receptor activation by linking an extracellular ligand-binding domain specific for a tumor cell surface antigen to an intracellular signaling module. The T-cells are then activated once antigen binding has occurred and execute their cytotoxic effector functions killing the tumor cells. 

In multiple myeloma (MM) there were several studies on CAR T-cell therapies. In the CARTITUDE-1 study patients treated with JNJ-4528 had overall response rates of 100% were reported with excellent persistence and a central memory immune pattern of the T cells.  The phase I LEGEND study of the same drug reported with a median follow-up of 19 months that the median PFS (progression-free survival) was 28 months for patients with a CR (complete response) and MRD (minimal residual disease) negativity (at a sensitivity level of 10-5).

bb21217, a second generation anti-BCMA CAR T-cell design that enriches for memory T cells, was investigated in relapsed and refractory (RR) MM and reported similar efficacy and tolerability to the bb2121 product, which previously reported promising efficacy in RRMM. A total of 83% (10/12) of patients reported clinical responses and all patients evaluable for MRD testing were MRD negative (at a sensitivity level of 10-5).

Just as interesting as CAR T-cell therapy are BiTEs (bi-specific T-cell engager), which is a BCMA – T-cell engager called CC – 93269. This bispecific T-cell contains two arms to bind to BCMA on myeloma cells, and one arm to bind to T-cells. Results from 19 patients with RRMM who had received a median 6 prior lines of therapy were promising with regard to both efficacy and safety. A total of 12 patients were treated with ≥6 mg, 89% had ORR and 9 of these patients were MRD-negative (at a sensitivity level of 10-5).

In Lymphoma, there are currently two CAR T-cell products approved for treatment but more are in development. The TRANSCEND NHL 001 study reported of lisocabtagene maraleucel in RR diffuse large B-cell lymphoma reported that among 255 evaluable patients ORR were 73% and the CR rates were 53%.

Treatment options for patients relapsing after CAR T-cell therapy are limited, but a study of mosunetuzumab – a bispecific antibody targeting both CD3 (on the surface of T-cells) and CD20 (on the surface of B-cells) – in patients who had received a median 3 prior lines of therapy reported ORR of 64.1% and CR rates of 42.2% with lasting responses and tolerable safety in 218 evaluable patients who had progressed following CAR T-cell therapy. 

One of the challenges with CAR T-cell therapy is the time needed to manufacture the CAR T-cells, during which patients often progress and in some cases may be too sick to receive treatment. FT596 is among the cellular immunotherapies to be based on off-the-shelf NK cells so the therapy would be available immediately. Results from a pre-clinical study reported that FT596 was able to kill cancerous white blood cells and when combined with rituximab, white blood cells that were no longer responding to standard CAR T-cell therapy (due to loss of the CD19 antigen target) were killed. Trials in B-cell lymphoma and chronic lymphocytic leukemia are expected to begin next year.