CAR-T versus bispecific antibodies and BiTEs in multiple myeloma

Chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (bsAbs)/bispecific T-cell engagers (BiTEs), even though they present structural similarities, differ in their mode of action. CAR-T therapies rely on ex vivo activated and expanded T cells, whereas bsAbs/BiTEs count on the patient’s endogenous T cells.

During the 3rd European CAR T-cell Meeting, Sébastien Anguille discussed some true and false statements about CAR-T and bsAbs/BiTEs in multiple myeloma (MM).¹ Test your knowledge below and review some of the most critical aspects when comparing these two cutting-edge therapies.

Poll 1

There are at least 23 different B-cell maturation antigen (BCMA)-targeted CAR-T products and seven different bsAB/BiTEs directed to BCMA in clinical development.¹

The three most advanced BCMA CAR-T products are ide-cel, cilta-cel, and orva-cel; ide-cel being the first CAR-T in MM approved by the FDA. The BCMA-directed bsAbs/BiTEs are still in phase I clinical trials.¹

This statement is definitely true.

Their administration is also different: CAR T cells are usually administered as a single intravenous infusion, whereas most of the bsAbs/BiTEs, due to their very short half-life, need to be administered intravenously or subcutaneously once weekly.¹

Poll 2

Of 639 patients treated with the 23 different BCMA CAR-Ts, 80.3% experienced cytokine release syndrome (CRS) of any grade and 14.1% of Grade ≥3; whereas of the 359 patients treated with the seven different BCMA bsAbs/BiTEs, 55.2% experienced CRS of any grade, and only 2.8% had Grade ≥3 CRS.²

Table 1 shows the percentage of patients experiencing CRS and neurotoxicity, the median time of onset, and the median duration of CRS with BCMA CAR-T products and BCMA bsAbs/BiTEs. Patients treated with bsAbs/BiTEs experienced CRS events earlier, but they were less long-lasting than those experienced with CAR-T.¹ Besides, even though the administration of bsAbs/BiTEs is not a one-time event (unlike CAR-T), CRS events usually occur in the first administration. As observed for CRS, neurotoxicity is also less frequent with bsAbs/BiTEs, except for PF-3135, which shows a neurotoxicity rate comparable to that observed with CAR-T (20%).¹

Fewer CRS and neurotoxicity events were observed with bsAbs/BiTEs; hence, to date, this statement is true.

Table 1. CRS and neurotoxicity with BCMA CAR-T and bsAbs/BiTEs¹

BiTE, bispecific T-cell engager; bsAb, bispecific antibodies; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; d, day; hr, hour; ND, not determined; NT, neurotoxicity. *Data reported for subcutaneous cohort only.
	CAR-T			bsAbs/BiTEs
	Ide-cel	Cilta-cel	Orva-cel	AMG420	AMG701	REGN 5458	TNB-383B	CC-93269	PF-3135	Teclistamab
N	128	97	62	42	85	49	58	30	30	n = 65*
CRS	84%	95%	89%	38%	65%	39%	45%	77%	73%	57%
Median time of onset, (range)	1 d (1─12)	7 d (1─12)	2 d (1─12)	ND	ND	18 hr (6 hr─16 d)	<24 hr (<24 hr─7 d)	24 hr (24 hr─9 d)	<48 hr (ND)	48 hr (1─5 d)
Median duration, d (range)	5 (1─63)	4 (1─97)	4 (1─10)	ND	ND	0.5 (0─3)	1 (1─7)	2 (1─6)	2 (0─9)	2 (1─8)
NT	18%	21%	13%	7%	ND	12%	2%	0	20%	5% (N = 149)

Poll 3

A systematic review and meta-analysis of the BCMA CAR-T clinical trials showed that of 630 treated patients, 80.5% had an objective response, with 44.8% achieving a complete response (CR).² Among the BCMA CAR-T products, cilta-cel showed the highest CR rates (67% vs 33% for ide-cel vs 36% for orva-cel).¹ Efficacy reported with BCMA bsAbs/BiTEs is lower and less deep, with 41.4% of 345 treated patients demonstrating an objective response (Figure 1).¹

BiTE, bispecific T-cell engager; bsAb, bispecific antibody; CAR-T, chimeric antigen receptor T cells; CR, complete response; VGPR, very good partial response.

It is important to note that BCMA bsAbs/BiTEs have been evaluated mainly in phase I dose-finding clinical trials, and some patients were treated with suboptimal doses. When analyzing separately patients treated at top dose level or with the recommended phase II dose (n = 93), the objective response rate increases to 75%, with 26% of patients achieving a CR, 33% a very good partial response, and 16% a partial response (Figure 2). Here, it is possible to appreciate a similar efficacy between CAR-T and bsAbs/BiTEs, although this will need confirmation in future phase II trials. Thus, to date, this statement is false. They show similar ORRs in advanced MM.

BiTE, bispecific T-cell engager; bsAb, bispecific antibody; CR, complete response; PR, partial response; VGPR, very good partial response.

Conclusion

• CAR-T and bsAbs/BiTEs share similarities but they constitute different therapeutic classes
• BCMA is the most popular target antigen, both in the context of CAR T-cell therapy as well as in the context of bsAbs/BiTEs
• CAR T-cell therapies are more advanced for the treatment of MM than bsAbs/BiTEs
• bsAbs/BiTEs seem to have a more favorable safety profile in terms of CRS events and neurotoxicity
• Although these are indirect comparisons, bsAbs/BiTEs seem to have an efficacy comparable to CAR-T in the relapsed/refractory setting