Designing a strong bridge to CAR-T cells with bispecifics Free

In this issue of Blood, Dhakal et al¹ performed a multi-institutional retrospective analysis evaluating talquetamab, a G-protein–coupled receptor, family C, group 5, member D (GPRC5D)–targeting bispecific antibody (BsAb), as bridging therapy before chimeric antigen receptor T-cell (CAR-T) therapies against B-cell maturation antigen (BCMA), either idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel; see figure).

Ide-cel and cilta-cel are the 2 anti-BCMA CAR-T products currently approved in the United States and Europe. Despite unprecedented responses in relapsed/refractory multiple myeloma (RRMM),^2,3 the long manufacturing time (6-8 weeks) may limit the applicability of this approach in heavily-pretreated patients, who are usually multidrug refractory and have aggressive disease at relapse. Approximately 10% to 15% of patients undergoing lymphocyte apheresis with the intent to infuse CAR-T do not receive it most frequently due to disease progression/death during CAR-T manufacturing.² 

In this context, effective bridging therapy is often critical in avoiding disease progression and clinical deterioration that may preclude CAR-T infusion. Moreover, a good response to bridging therapy means low disease burden at the time of CAR-T infusion, which correlates with better outcomes and potentially reduced toxicity.⁴ In the CARTITUDE-4 trial, when cilta-cel was given after 1 to 3 prior lines, lower rates of cytopenia, cytokine release syndrome (CRS), and CAR-T–related neurotoxicity were observed than those in the CARTITUDE-1 trial enrolling patients after ≥3 lines of therapy.⁵ This may be explained at least in part by the availability of an effective bridging therapy in earlier lines.

An ideal bridging therapy should provide debulking, act rapidly, not add to the risk of resistance toward the CAR-T target, and not induce toxicities that may be additional to the ones of the CAR-T therapy itself.

Recently, GPRC5D emerged as a new immunotherapeutic target in MM. Talquetamab is currently the only GPRC5D-targeting BsAb approved for RRMM treatment in the United States and Europe. In the MonumenTAL-1 phase 1 to 2 study, talquetamab induced a 69% to 74% overall response rate in heavily-pretreated patients.⁶ Responses were fast, with a median time to very good partial response (VGPR) of 1.9 to 2.2 months. Risk of infection as well as on-target off-tumor adverse events (AEs; eg, skin related, nail related, taste changes, and weight loss due to GPRC5D expression in normal epithelial tissue) may limit long-term duration of talquetamab treatment. The speed and high rate of response to talquetamab in heavily-pretreated patients, its target (GPRC5D rather than BCMA), and the potential lower toxicity with short-term therapy make the drug an appealing option as bridging therapy before anti-BCMA CAR-Ts in late lines.

In the retrospective multicenter study of 134 patients by Dhakal et al, bridging therapy with talquetamab was administered for a median of 23 days: with this short-term treatment, 71% of patients responded (with 40% achieving VGPR or better). Talquetamab-related grade ≥3 CRS was not observed, and grade ≥3 neurotoxicity was seen in only 2% of patients. Nevertheless, despite the short treatment course, low-grade (1-2) on-target off-tumor AEs were quite frequent (70% oral, 38% skin, 17% nail, and 15% weight loss).

After talquetamab bridging, 89% of patients received CAR-T. Among 15 patients who did not receive CAR-T, 7 had rapid disease progression, whereas 6 had manufacturing failure. Two of the 6 patients with manufacturing failure also received talquetamab before apheresis. Indeed, a highly and rapidly effective off-the-shelf therapy such as talquetamab may also be helpful before apheresis to control the disease. Only 19 patients (14%) received talquetamab before T-cell collection, with talquetamab being held for 2 to 4 weeks before apheresis. Indeed, BsAbs induce rapid T-cell activation, and repeated infusions may cause T-cell exhaustion,⁷ making T cell less fit to undergo CAR-T manufacturing. In this light, in cases of rapid and aggressive relapses, the risk/benefit of continuing an off-the-shelf therapy such as BsAbs without subsequent CAR-T⁸ needs to be evaluated. Other options currently under investigation including autologous CAR-T with shorter manufacturing time or allogeneic CAR-T may be alternatives in the future.

Among the patients receiving CAR-T, the overall response rate at 1 month after infusion was 88% (71% VGPR or better) and at a median follow-up of 4.2 months, 42% of patients deepened the response obtained with talquetamab. Due to the monoclonal protein half-life, it is difficult to precisely determine how much the deepening of response was due to CAR-T and how much was a late response to talquetamab. Progression-free survival, despite promising, is still immature. Extramedullary disease (EMD) was the only factor negatively affecting outcome. Recently, encouraging results in this setting have been described with association of anti-BCMA + anti-GPRC5D BsAbs,⁸ suggesting that simultaneous rather than sequential targeting of BCMA and GPRC5D may be the best strategy in patients with EMD.

Regarding CAR-T safety, low-grade toxicities were common, but only 2% grade ≥3 CRS and 1% grade 3 immune effector cell–associated neurotoxicity syndrome (ICANS) were observed. These results compared favorably with the KarMMa-1 and Cartitude-1 trials.^2,3 Therefore, the sequential approach with BsAbs followed by CAR-Ts does not seem to increase the risk of severe CRS/ICANS. Of note, no infections were observed during talquetamab bridging, and only 5% grade 3 to 4 infections were reported after CAR-T infusion. Longer follow-up is needed to better determine the infection rate and possible late toxicities.

For patients with talquetamab-associated toxicities, 60% of patients had complete resolution. The remaining 40% had still talquetamab-associated AEs, mainly nail and taste changes. However, in MonumenTAL-1,⁶ these AEs had a median duration of ∼3 to 6 months, meaning that with longer follow-up the percentage of patients with complete resolution could increase.

The short course of talquetamab treatment used in this study may represent an opportunity of re-treatment with anti-GPRC5D immunotherapies in case of relapse after anti-BCMA CAR-T. Indeed, GPRC5D loss is described in most patients progressing while on talquetamab continuous treatment,⁷ but it may be less frequent with fixed-duration, short-course therapy.

In conclusion, data from this real-life experience may be the proof of concept of a sequential BsAb–CAR-T approach. GPRC5D CAR-Ts are currently in clinical development,⁹ and a bridging therapy with anti-BCMA BsAbs may be an effective therapy in this context as well, warranting further investigation.

Conflict-of-interest disclosure: F.G. reports honoraria from Amgen, Janssen, Takeda, Sanofi, Bristol Myers Squibb/Celgene, AbbVie, Pfizer, and GlaxoSmithKline and advisory board fees from Amgen, Janssen, Takeda, Pfizer, Sanofi, Bristol Myers Squibb/Celgene, Oncopeptides, Roche, AbbVie, GlaxoSmithKline, AstraZeneca, Regeneron, and Gilead/Kite. M.D. reports honoraria from GlaxoSmithKline, Sanofi, and Janssen; advisory board fees from GlaxoSmithKline, Sanofi, Bristol Myers Squibb, and Adaptive Biotechnologies; and research support from Janssen.