Andrew Spencer, MBBS, FRACP, FRCPA, DM, breaks down phase 1 data for in vivo CAR T-cell therapy in relapsed/refractory multiple myeloma.
With in vivo CAR T-cell therapy representing a potential way reduce logistical treatment challenges associated with currently approved autologous products, additional data on response durability using an in vivo approach will be pivotal for moving this modality forward in the multiple myeloma treatment paradigm, according to Andrew Spencer, MBBS, FRACP, FRCPA, DM.
“If [these early data] hold true, this is a complete game changer in the myeloma treatment space,” Spencer said in an interview with OncLive®.
During the
In the interview, Spencer expanded on the logistical hurdles that in vivo CAR T-cell therapy could help address, outlined key efficacy and safety data reported from inMMyCAR, and detailed how in vivo treatment could fit into the paradigm in the future.
Spencer is a professor of hematology at Monash University and head of the Malignant Haematology, Transplantation, and Cellular Therapy Service and the Myeloma Research Group at The Alfred Hospital in Melbourne, Australia.
Spencer: It is fundamentally [a] different paradigm in that it's a gene therapy [that] promotes the in vivo generation of BCMA[-targeted] CAR T cells, therefore it side steps a lot of the logistical problems that we have with autologous CAR T-cell therapies. There's no cell collection, there's no manufacturing, [and] there's no lymphodepletion. Instead of waiting 4 to 6 weeks [for CAR T-cell therapy manufacturing], theoretically, this can happen within days, which has obvious advantages for the patient, because a substantial proportion of patients will [have cells] collected and never make it to [CAR T-cell therapy infusion] because of disease progression. The whole logistical side of it is sort of removed [with an in vivo product]. The challenges are removed, the real question now is the deliverability, safety, and the durability of responses [with in vivo CAR T-cell therapy].
[inMMyCAR enrolled] a fairly standard relapsed or refractory myeloma population: at least 3 prior lines [of therapy and] triple-class exposed. That's the population in which a lot of early [drug] development moves into first. It was a 3+3 dose-escalation phase 1 study with backfill, and one of the most important things about this was we were incredibly sensitive around patient selection, because [in vivo CAR T-cell therapy] was a bit of an unknown. The safety element was massive, we tried to [enroll] patients who were clearly eligible but weren't in a state where the disease was going to be problematic in the time frame that we were studying.
[Additionally,] because we saw significant activity with the first dose level, unlike most phase 1 steps, we actually de-escalated to dose level –1 and dose level –2, and we still saw activity. [There were] some initial infusion reactions that we determined a small dose dexamethasone premedication abrogates completely. We haven't seen any more since [adding dexamethasone premedication].
One of the theoretical concerns about in vivo CAR T-cell generation is that there may be patients who, phenotypically, you simply can't get generation or expansion of CAR T cells, unlike the autologous current paradigm, where you've sort of got the cells in the lab and you can manipulate and expand. [In vivo generation] is completely out of your control, and in the patients I spoke about [during EHA 2026], it had been demonstrated that from the T cell immunophenotype, both in quantity and quality, there was marked variation across the patient population, and in fact that did not have an impact on the ability to get CAR T expansion. That was reassuring.
The [current] numbers are insufficient to make any call about whether there were certain subsets of patients whose [disease] behaved differently, but over time, of course, that data will be generated and looked at. What was important [in these EHA 2026 data], even though it wasn't the primary end point of the study, was that at the 1-month time point, all patients who had results available [were] MRD negative at the 10-5 level. That was a bit mind-blowing. We didn't really anticipate that level of activity. Out of all [18] patients [treated] so far, there has been 1 patient who progressed and 1 patient who's lost their MRD negativity. The reality is there's never going to be a therapy that has 100% efficacy [and is] durable, but based on these efficacy signals and pharmacodynamic studies looking at the phenotype of the generated cells and the expansion, [these data are] very, very positive.
We did see cytokine release syndrome in a lot of patients, but it was low-grade and relatively easy to manage. I've seen 2 cases of immune effector cell–associated neurotoxicity syndrome. The interesting thing is that these short-term immunological issues occur slightly later than what we've seen with commercial [autologous] CAR T-cell therapy, because when you look at the kinetics of the expansion, it's actually later with [KLN-1010] than with the autologous cells. In the short-term, things look good, but undoubtedly when the population [size] increases, we're going to see more immunological issues.
The [big] question is: [Will the safety of KLN-1010 be] comparable to the currently available products? If so, that's okay, as long as it's not obviously worse. Are we going to see those medium- to long-term neurological issues that are seen in some patients [with current CAR T-cell therapies]? I suspect the answer is going to be no. We've got some patients out to 9 months—only a small number—but we've not seen anything, so fingers crossed that picture will be maintained.
One of the issues with myeloma is that [almost everyone is] treated the same way, which is scientifically vacuous, to be quite frank. It's a very heterogeneous disease. My hope would be that if this treatment paradigm plays out successfully, [in vivo CAR T-cell therapy] will replace autologous CAR T, and hopefully it's a therapy that would be made available early in the treatment [course]. Depending on the safety profile, you'd have to be prudent about [for whom] you may use this [agent]. It could be a real boon if it proves to be durable and is brought up earlier in the treatment algorithm.
