A Perspective on Immunotherapy Studies Presented at ASH 2018

In a continuation of the theme for ASH 2018, this summary is dedicated to immunotherapy. The next wave of chimeric antigen receptor (CAR) T cells is here, with a focus on next-generation designs or newer targets. Examples include dual-targeted CAR T cells aimed at CD19 and CD22 highlighted in the acute lymphoblastic leukemia (ALL) and aggressive non-Hodgkin lymphoma (NHL) sessions or “armored” CAR T cells that have novel co-stimulatory activation domains and configuration. Perhaps what was most novel was presented by the Chinese group with what they are calling 4SCAR2.0 (abstract 225). They quite rightly point out that a key mechanism of resistance to single-targeted CAR T cells is loss of antigen. As a result, they have developed a protocol wherein they examine a lymphoma patient’s disease for the presence of four biomarkers: CD19, CD22, CD70, and PSMA. Their thinking is that the disease will likely express a combination of two of the four markers which they can then adapt the CAR T-cell manufacturing to target these two markers. Their CAR T cell also incorporates a ‘suicide gene’ that can be used to inactivate the CAR T cell, but their patients did not observe any severe toxicity that necessitated its use. That was an important observation because on top of the novel targeting, they also employed a second booster (and lower) dose of CAR T cells seven days after the first normal, therapeutic dose. In a non-standardized analysis, they found that this double dose produced a complete response (CR) rate of 95% versus 50% in those receiving a single dose. I highlight this particular abstract because it demonstrates multiple different strategies where the field is moving into such as precision medicine, modified dosing, and inactivating methods. Time is still needed to determine whether these methods and subsequent impressive responses are durable and translate into long-term remissions.

Looking beyond CAR T cells, other immunotherapy agents are showing promise. Blinatumomab, a bispecific T-cell engager (BiTE) is a standard therapy for salvage of ALL patients. More recently, its use in B-cell lymphomas has been explored with strong activity in relapsed diffuse large B-cell lymphoma (DLBCL). Abstract 400 presented early data of a phase II study where investigators moved blinatumomab higher up in treatment of relapse DLBCL. In this study, patients received blinatumomab as part of salvage therapy following relapse after frontline rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in a unique way. Patients were first given two cycles of platinum-containing salvage therapy. If they did not respond with a complete metabolic response based on positron emission tomography/ computed tomography imaging, they then proceeded to receive one cycle of blinatumomab. If a CR occurred after one cycle, then patients went onto autologous stem cell transplant (ASCT). If not, then a second cycle was given. Out of 41 patients treated, 15 patients responded (response rate of 36.6%) with 22% achieving CR. There was no clear subgroup that benefited better (i.e., germinal center B-cell subtype, limited versus advanced stage, performance status, etc.). Minimal survival data was available presently. Fifty-six percent of patients observed a neurologic toxicity and 24% of patients had a grade 3 or higher neurologic event. Only one cytokine release syndrome was seen. Taken together, I think this study demonstrates that blinatumomab is active in this setting, but a better strategy as to how to implement it is likely needed. Patients who have a partial response following platinum-based salvage can still go on to have a good response to ASCT. Further, a school of thought exists to suggest that a quick transition to transplant following salvage may also benefit patients – so adding a cycle of blinatumomab would only delay that. Lastly, blinatumomab has a very short half-life by virtue of being two linked single-chain variable fragments, meaning that it has to be given as a continuous infusion. Alternatively, a growing group of full-length bispecific antibodies for lymphoid and plasma cell malignancies is making their way into trials. Two examples presented are RG 6026 (abstract 226) and mosunetuzumab (abstract 399). Both are bispecific CD20/CD3 full-length antibodies with the exception that RG 6026 has a novel structure in that it contains two CD20 binding domains. RG 6026 was investigated in a phase I dose-escalation study of 98 multiply relapsed aggressive lymphoma patients. Patients received obintuzumab cytoreduction therapy first prior to RG 6026 treatment. Overall, the study drug was reasonably well tolerated with 55% of patients observing severe adverse events (AEs), but only a third of the population had treatment-related AEs. AEs of interest included cytokine release syndrome in 39% of patients (but none were grade 3 or higher) and neurotoxicity in 25% of patients (5% grade 3 or higher). Objective response rate (ORR) was 55% at clinically meaningful doses, with 25% CRs. Mosunetuzumab, alternatively in a traditional antibody structure, was also active in its phase I study but included additional indolent histologies. As a result, it is difficult to compare them. In this mixed NHL study, ORR was 41%. It had similar reasonable tolerability with comparable low-grade cytokine release and neurotoxicity.

This summary is just a brief snapshot regarding the explosion of immunotherapy in hematologic malignancies presented at ASH 2018. For the sake of brevity, I did not cover all of the compounds presented, but certainly CAR T cells and bispecific antibodies appear to be the most promising presently. That is not to say that more ‘traditional’ technologies are not still active. I will briefly point out abstracts 398 and 227 looking at the activity of loncastuximab tesirine, a novel antibody drug conjugate, and MOR208, an anti-CD19 monoclonal antibody, in relapsed lymphoma. Both studies showed good activity of each drug and are worth keeping an eye out for in the future.