An influx of bispecific T-cell engagers, CAR T-cell therapies, and antibody-drug conjugates have revolutionized the treatment of hematologic malignancies; however, with several options in the sandbox, accessibility and unexplored clinical questions present challenges for optimal integration of these options into treatment.
An influx of bispecific T-cell engagers (BiTEs), CAR T-cell therapies, and antibody-drug conjugates (ADCs) have revolutionized the treatment of hematologic malignancies. However, with several options in the sandbox, Andrew D. Zelenetz, MD, PhD, noted that accessibility and unexplored clinical questions present challenges for patients and clinicians for optimal integration into treatment regimens.
“If we’re going to have multiple [treatments], we have to [be able to] access to them,” Zelenetz, medical director of quality informatics at Memorial Sloan Kettering Cancer Center in New York, New York, said in a presentation during the 2022 Pan Pacific Lymphoma Conference.1
Zelenetz added that the lowest barrier to access is for ADCs largely because institutional set up for administration would be minimal. “But with CAR T cells and [BiTEs], that is different. There is a significant learning curve for multiple parts of an institution. There [must] be appropriate medical expertise, pharmacy expertise, nursing expertise, and administration has to be willing to support it. With CAR T-cell therapy, an institution [must] go through the process of accreditation and dedicate institutional resources in terms of location and space for appropriate cell processing facilities. They have to an institution has to have the right financial payer mix to make this worthwhile. Many of those are true for BiTEs, [and although] there is a little less of an [ask for] institutional research, there is still a resource commitment. You do not have the accreditation factor, and you do not have the significant space allocation that is necessary for cellular therapy, but both of these products have substantial learning curves, and are going to limit access.”
Presenting with the lowest hurdle to integration, ADCs have demonstrated efficacy in relapsed or refractory diffuse large B-cell lymphoma (DLBCL), multiple myeloma, Hodgkin lymphomas, and B-cell precursor acute lymphoblastic leukemia (ALL).
In describing the ideal construction for an ADC, Zelenetz highlighted that an antibody must have high tumor/normal target antigen expression, no shedding of antigen after antibody binding, be suitable for internalization of the payload, have favorable stoichiometry, and low immunogenicity. Linkers for the compound must be stable, readily cleavable, and not impair the antibody binding. Further, the conjugate drug must be highly potent at low concentration, improve the therapeutic margin compared with the free drug, and be soluble in aqueous solutions.
Zelenetz said that all of these characters may not be possible, but that the more boxes that are checked off there is a higher likelihood of mitigating off-target toxicities. “The antibody has to have some [of these] characteristics. It’d be nice [if it was] expressed on the tumor, and not so much on normal tissue. This is not always possible. Sometimes, we can wipe out a lineage and not all cells and it would be good if it does not shed, because if it sheds, then the antibody is going to bind in the in the serum and you are going to get toxicity as a result,” he explained.
In looking at ideal targets for ADCs, Zelenetz discussed the expression of surface antigens across malignancies. “If you look at CD20 just hangs around and stays on the cell surface. It’s probably not good for an ADC that you want to get in the cell. But if you look at CD22 and CD19, these are internalizing rapidly and a much more have much more favorable biology as potential targets.” Zelenetz provided an overview of the approved agents across malignancies noting, “This is a proven, safe and efficacious pathway for delivering drugs.”
For example, an ADC targeted against CD22, inotuzumab ozogamicin was approved in 2017 for the treatment of adults with relapsed or refractory B-cell precursor ALL.2
Investigators of the phase 3 INO-VATE ALL trial (NCT01564784) randomly assigned patients with Philadelphia chromosome (Ph)-negative or Ph-positive relapsed or refractory B-cell precursor ALL with at least 5% bone marrow blasts to either inotuzumab ozogamicin (n = 164) or investigator’s choice of chemotherapy (n = 162). The complete remission rate was 35.8% with inotuzumab ozogamicin experienced complete remission (CR) with a median duration of response of 8 months compared with 17.4% CR rate for a median of 4.9 months with chemotherapy. Minimal residual disease negativity was achieved by 89.7% and 31.6% of patients, respectively.
ADC payloads are largely chemotherapy agents with a negative therapeutic index and the targeted delivery allows for efficacy at the tumor with limitation of the toxicity, Zelenetz said. Prospective randomized trials have shown that ADCs combine well with conventional chemoimmunotherapy.
For example, the addition of the CD79b-directed ADC polatuzumab vedotin-piiq (Polivy) to rituximab (Rituxan), cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) demonstrated significant improvements in progression-free survival vs rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Findings from the phase 3 POLARIX trial (NCT03274492) were presented in a poster during the meeting.3
At 2 years, the PFS rate was 76.7% (95% CI, 72.7%-80.8%) vs 70.2% (95% CI, 65.8%-74.6%) in the experimental and control arms, respectively, (HR, 0.73; 95% CI, 0.57-0.95; P = .02).3
Zelenetz noted that these agents may have the potential to be combined with BiTEs and that chemotherapy may be included if it not T-cell toxic. However, there is less support for combining ADCs with CAR T-cell therapy, and Zelenetz said he would need more preclinical data to support this approach.
He also noted that ADCs have been inadequately evaluated in follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia.
In the discussion of BiTEs, Zelenetz noted that this class of agents has a wide the array of different antibodies and constructs. “There are a large array of possible constructs here, [but] how do we get the bispecifics to the tumor? We can give it [intravenously (IV)], so we have things like blinatumomab [Blincyto], given by [IV], it’s going to recruit T cells. But we can take an approach and try to deliver it with what are called armored CAR T cells.” Zelenetz explained that this process would introduce the contrast to the CAR T cell with the ability to then recruit additional T cells, and augment to the effectiveness of CAR T cells.
Another approach is through an oncolytic virus. “This is injected into the tumor, the tumor then produces the bispecific antibody, and that actually attracts tumor cells and acts locally. Lots of different approaches for delivering the bispecific,” Zelenetz said.
One agent with demonstrated efficacy is epcoritamab (GEN3013), a CD3 x CD20 antibody with a duobody IgG1 bispecific format. Among patients with highly refractory large B-cell lymphoma, including those who were previously treated with CAR T-cell therapy, the agent demonstrated deep and durable responses: overall response rate, 63% with a CR rate of 39% according to data from the phase 2 EPCORE NHL-1 clinical trial (NCT04663347).4
CAR T-cell therapy is well established for patients with relapsed or refractory DLBCL, Zelenetz said, adding that questions for this patient population are limited to its role as a first-line therapeutic option.
Axicabtagene ciloleucel (Yescarta) and lisocabtagene maraleucel (Breyanzi) have both demonstrated benefit in early relapse disease, with the both having indications for patients with disease that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.5,6
Unanswered questions in this space include the role of CAR T-cell therapy for patients with follicular lymphoma or mantle cell lymphoma. Long-term follow-up data are needed to support the superiority of alternative approaches.
Access to CAR T-cell therapy remains a large problem in the United States, Zelenetz said. “If you need CAR T-cell therapy, approximately 20% of [individuals] are going to travel less than 10 miles. And 40% of [individuals] are going to have to travel more than 60 miles to get there. We also see that there are significant differences in availability by race, and by socioeconomic status. We have serious barriers to access to these therapies.”
Zelenetz said in his concluding remarks that limited data is one of the largest hurdles for sorting through the sandbox of available agents. “Third line and beyond the bispecifics data and CAR T-cell therapy are looking very exciting in large cell lymphoma. We are curing patients, certainly with the CAR T cells and potentially with bispecifics,” he said.
“This sandbox is filled with a lot, [but] not a lot of available data. Why? Because we just haven’t done the appropriate studies,” he said. “Bispecifics are demonstrating substantial exciting activity in follicular lymphoma [and] their movement into the front line is inevitable. We will see randomized trials that will tell us whether these will in fact become part of standard of care. But we’re really lacking data in mantle cell lymphoma, marginal zone lymphoma, and CLL where we really would like to see substantial, more effort into these diseases.”