Second-line tisa-cel similar to standard-of-care for R/R aggressive non-Hodgkin lymphoma

The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (tisa-cel) as second-line treatment did not improve event-free survival (EFS) of patients with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma compared with standard-of-care [1]. These results of the phase 3 BELINDA study contradict previous CAR T-cell therapy trials that have shown improved clinical outcomes.

Tisa-cel, an autologous CAR T-cell therapy targeting CD19, is approved for patients with diffuse large B-cell lymphoma (DLBCL) after ≥2 lines of therapy [2,3]. Dr Michael Bishop (University of Chicago, IL, USA) presented the results of the BELINDA trial (NCT03570892), which enrolled 322 adults with confirmed R/R aggressive non-Hodgkin lymphoma within 12 months after first-line chemo-immunotherapy. All patients underwent leukapheresis for tisa-cel production and were randomised 1:1 to receive tisa-cel (arm A) or standard-of-care (arm B). Patients in arm A could receive bridging therapy, defined as an investigator choice of protocol-defined platinum-based chemotherapy, followed by lymphodepletion and a single tisa-cel infusion. Responders in arm B received investigator choice of platinum-based chemotherapy regimen followed by autologous haematopoietic cell transplantation in responders, and non-responders received a second platinum-based chemotherapy. The primary endpoint was EFS, defined as death at any time or progressive or stable disease at or after 12 weeks.

The median EFS was 3 months in both arms (HR 1.07; 95% CI 0.82–1.40; P=0.69). At week 12, the overall response rate (ORR) was 46% in arm A versus 43% in arm B. The complete response rate was 28% in both arms. A higher proportion of patients had progressive disease at week 6, prior to CAR T-cell infusion, in the tisa-cel arm.

“Our findings suggest the importance of preventing progressive disease prior to CAR T-cell infusion,” Dr Bishop concluded. Moreover, effective bridging prior to CAR T-cell infusion and a shorter time to infusion for this chemotherapy-refractory patient population could be critical to improving outcomes.

  1. Bishop MR. Tisagenlecleucel Vs Standard of Care As Second-Line Therapy of Primary Refractory or Relapsed Aggressive B-Cell Non-Hodgkin Lymphoma: Analysis of the Phase III Belinda Study. LBA-6, ASH 2021 Annual Meeting, 11–14 December.
  2. Maude SL, et al. N Engl J Med 2018;378:439–448.
  3. Schuster SJ, et al. N Engl J Med 2019;380:45–56.
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CAR-Hematotox score predicts toxicity, infections, and clinical outcomes in MCL

Patients with relapsed or refractory mantle cell lymphoma (MCL) and a high CAR-Hematotox score had an increased risk for haematological toxicity, infections, and an inferior progression-free survival and overall survival following treatment with brexucabtagene autoleucel (brexu-cel). According to the authors, stratifying patients for the risk of haematological toxicity may aid physicians to tailor the management of their patients.

CAR T-related haematological toxicity is a frequently occurring phenomenon, and prolonged cytopenia and complications due to infections contribute to the toxicity burden of CD19-directed CAR T therapy [1]. “The CAR-Hematotox score predicts the risk for prolonged neutropenia, severe infections, and poor treatment outcomes after CD19 CAR T-cell therapy,” said Dr Kai Rejeski (LMU Munich, Germany) [1,2]. The use of this tool in patients with relapsed/refractory MCL undergoing CD19 CAR T-cell therapy has not yet been established. Therefore, the current international, multicentre, retrospective study analysed the applicability of the CAR-Hematotox score in 103 patients with relapsed/refractory MCL receiving brexu-cel.

At baseline, high CAR-Hematotox scores (HT-high) were related to aggressive disease biology, increased bone marrow infiltration, a higher number of prior treatments, and increased disease activity. It was demonstrated that patients with HT-high had higher risk for haematologic toxicity than patients with HT-low: neutropenia (median 14 vs 6 days; P<0.001); aplastic phenotype (47% vs 0%; P<0.001); severe anaemia (45% vs 11%; P<0.0001); profound (85% vs 46%; P<0.0001) or prolonged cytopenia (66% vs 30%; P<0.0004). Furthermore, severe infections were more common in HT-high patients than in HT-low patients (30% vs 5%; P=0.001), mostly driven by an increase in bacterial infections (28% vs 5%; P=0.002). Finally, after 720 days of follow-up, HT-high scores were associated with poorer progression-free survival (38% vs 79%; P<0.0001) and overall survival (52% vs 90%; P=0.00016).

In summary, HT-high patients had an increased risk to develop severe haematotoxicity and infectious complications and had a reduced progression-free and overall survival compared with HT-low patients. Dr Rejeski commented that a risk stratification for haematological toxicity and infections should be performed before lymphodepletion in order to initiate prophylactic strategies in time.

  1. Rejeski K, et al. Blood. 2021;138(24):2499–2513.
  2. Rejeski K, et al. The CAR-Hematotox Score Identifies Patients at High Risk for Hematological Toxicity, Infections and Poor Clinical Outcomes Following BrexucabtageneAutoleucel in Relapsed/Refractory Mantle Cell Lymphoma. Abstract 264, ASH 64th Annual Meeting, 10–13 December 2022, New Orleans, LA, USA.
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CAR-Hematotox score proves useful in relapsed/refractory MM

In patients with relapsed/refractory multiple myeloma (MM) receiving BCMA-directed CAR T-cell therapy, high CAR-Hematotox scores (HT-high) were associated with an increased risk for severe haematotoxicity, severe infections, and a reduced progression-free survival (PFS) and overall survival (OS) in this retrospective study. According to the authors, these results suggest that the CAR-Hematotox score can be used to drive risk-adapted management strategies for these patients.

“Prolonged cytopenia and infectious complications substantially contribute to the toxicity burden of CD19-directed CAR T-cell therapy,” explained Dr Kai Rejeski (LMU Munich, Germany). The CAR-Hematotox score was developed to estimate the risk for haematotoxicity, infections, and poor treatment outcomes after CD19-directed CAR T-cell therapy. Whether this tool has utility in patients with relapsed/refractory MM receiving BCMA-directed CAR T-cell therapy had not yet been established. Dr Rejeski and colleagues performed a retrospective analysis on patients with relapsed/refractory MM receiving either ide-cel or cilta-cel to assess the use of the CAR-Hematotox score in this population (n=113) [1].

HT-high scores at baseline were significantly associated with a poor performance status, high disease activity, prior autologous stem cell transplant, poor renal function, and increased bone marrow infiltration. Also, patients with HT-high scores had an increased risk for prolonged neutropenia compared with patients with HT-low scores (mean 9 vs 3 days; P<0.001). Other haematological toxicities were also more common among patients with HT-high scores (see Figure). Furthermore, the rate of severe infections was significantly higher in patients with HT-high scores than in patients with HT-low scores (40% vs 5%; P<0.0001), mostly driven by an increased rate of bacterial infections (34% vs 3%; P<0.0001). Finally, HT-high scores were linked to poorer PFS (median 5.4 vs 14.9 months; P<0.0001) and OS (median 10.5 vs not reached; P<0.0001) outcomes.

Figure: CAR T-mediated haematotoxicity in HT-high and HT-low patients [1]

Hb, hemoglobin; ANC, absolute neutrophil count.

  1. Rejeski K, et al. The CAR-Hematotox Score As a Prognostic Model of Toxicity and Response in Patients Receiving BCMA-Directed CAR-T for Relapsed/Refractory Multiple Myeloma. Poster 3343, ASH 64th Annual Meeting, 10–13 December 2022, New Orleans, LA, USA.
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Promising results for novel CAR-T therapy in relapsed/refractory multiple myeloma

GC012F, a dual CAR-T therapy, showed favourable safety outcomes and a high response rate in a population of patients with heavily pre-treated relapsed/refractory multiple myeloma (RRMM) in an update of the first-in-human study testing this BCMA/CD19-targeting therapy.

“FasTCAR GC012F is a CAR-T therapy that targets both BCMA and CD19 in order to establish fast, deep, and durable responses in patients with MM,” explained Prof. Juan Du (Shanghai Chang Zheng Hospital, China). With a time from isolation until freezing of only 22–36 hours, the current therapy establishes a fast vein-to-vein time, potentially eliminating the need for a bridging therapy prior to CAR-T infusion, which is often needed in conventional CAR-T therapy. The current, open-label, single arm, investigator-initiated trial subjected 28 patients with heavily pre-treated (≥3 lines of therapy) RRMM to GC012F dual CAR-T therapy. Safety was the primary endpoint of this study. Of note, 89% of the patients had a high-risk profile.

According to Prof. Du, the safety profile of the CAR-T therapy was favourable. Grade ≥3 haematologic adverse events ranged from 36% for anaemia to 82% for neutropenia. The cases of cytokine release syndrome were mostly low grade (0–2: 93%) and only 2 patients experienced a grade 3 cytokine release syndrome event. No cases of immune effector cell-associated neurotoxicity syndrome were reported.

In total, an impressive 89.3% of the patients responded to the therapy, with 75% of the patients displaying a minimal residual disease (MRD) complete response or stringent complete response and 86% of the patients demonstrating a very good partial response (VGPR) or better. In addition, after a median follow-up of 6.3 months, the median duration of response was not reached.

Prof. Du summarised that the updated results of this first-in-human study assessing FasTCAR GC012F dual CAR-T therapy showed very promising activity in a heavily pre-treated, high-risk population of patients with RRMM, with a favourable safety profile. “Fast, deep, and durable responses were achieved with this novel CAR-T therapy.”

  1. Du J, et al. Updated results of a multicenter first-in-human study of BCMA/CD19 dual-targeting fast CAR-T GC012F for patients with relapsed/refractory multiple myeloma (RRMM). Abstract 8005, ASCO 2022 Annual Meeting, 3–7 June, Chicago, IL, USA.
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Axi-cel more effective but tisa-cel less toxic in DLBCL

In a matched set population of patients with diffuse large B-cell lymphoma (DLBCL) who had received ≥2 lines of treatment, axicabtagene ciloleucel (axi-cel) resulted in a significantly prolonged progression-free survival (PFS) compared with tisagenlecleucel (tisa-cel). However, axi-cel was associated with significantly more frequent grade ≥3 neurotoxicity compared with tisa-cel. These results could help refine specific patient sub-populations who benefit most from each type of CAR T-cell therapy.

Axi-cel and tisa-cel are autologous anti-CD19 CAR T-cell therapies approved in the US and EU for adults with relapsed/refractory (R/R) DLBCL after ≥2 lines of systemic therapy. Dr Emmanuel Bachy (Hospices Civils de Lyon, France) and others conducted a propensity score-matched comparison of axi-cel and tisa-cel in a large cohort of R/R DLBCL patients treated outside of clinical trials. After a 1:1 ratio propensity score-matching, therapy outcomes were compared between 144 patients treated with axi-cel and 144 patients treated with tisa-cel. The primary endpoint was overall survival (OS).

After a median follow-up of 6.6 months, OS was not significantly different between axi-cel and tisa-cel at 6 months (78% vs 70% respectively; P=0.44; see Figure). Best overall and complete response rates were significantly higher with axi-cel compared with tisa-cel (73% vs 60%; P=0.02; and 56% vs 36%; P<0.001, respectively). At 6 months, PFS was significantly longer with axi-cel than with tisa-cel (53% vs 32%; P=0.011).

Figure: Overall survival with tisa-cel versus axi-cel [1]

Axi-cel, axicabtagene ciloleucel; OS, overall survival; tisa-cel, tisagenlecleucel.

With respect to the toxicity profile, there was no significant difference in the incidence of cytokine release syndrome (CRS), but axi-cel was associated with significantly more frequent neurotoxicity (ICANS) compared with tisa-cel, namely:

  • 6% vs 18.1% for grade 1–2 ICANS; and
  • 4% vs 2.1% for grade ≥3 ICANS (P<0.001).

After stringent propensity score-matching on a large patient population treated with CAR T-cell therapy, axi-cel resulted in higher response rates and significantly prolonged PFS compared with tisa-cel. However, greater efficacy came at the cost of higher neurotoxicity with axi-cel.

  1. Bachy E, et al. A Propensity Score-Matched Comparison of Axi-Cel and Tisa-Cel for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Real-Life: A Lysa Study from the Descar-T Registry. Abstract 92, ASH 2021 Annual Meeting, 11–14 December.
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High rate of rapid and complete responses with axi-cel in high-risk large B-cell lymphoma

ZUMA-12 is the first study evaluating CAR T-cell therapy as part of the first-line therapy in patients with high-risk large B-cell lymphoma (LBCL), defined by the histology and/or International Prognostic Index (IPI) and by dynamic risk assessment with PET scan [1]. In this population, axi-cel demonstrated a high rate of rapid and complete responses.

Patients with high-risk LBCL have poor outcomes, including lower response rates to available therapies and poorer overall survival (OS) outcomes [2]. Patients with early disease resistance after first-line rituximab (anti-CD20)-based chemoimmunotherapy, as assessed by dynamic PET scan, have an increased risk of death [3;4]. This highlights the need for novel treatments.

CAR T-cell therapy in R/R LBCL

Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, approved for the treatment of adults with relapsed/refractory (R/R) LBCL and adults with R/R follicular lymphoma, both after ≥2 lines of systemic therapy. A long-term follow-up analysis of axi-cel in refractory LBCL, presented at the ASH 2021 meeting, demonstrated a 5-year OS rate of 43% after a median follow-up of 63 months [5].

ZUMA-12 (NCT03761056) is a phase 2, multicentre, single-arm study investigating axi-cel as part of first-line therapy in patients with high-risk LBCL. Dr Sattva S. Neelapu (MD Anderson Cancer Center, Houston, USA) presented the efficacy, safety, and pharmacokinetic and pharmacodynamic (PK/PD) results from the primary analysis of this trial.

Improved outcomes

Eligible adults had high-risk LBCL, defined by histology or by an IPI score ≥3, in combination with a positive interim PET (Deauville score 4 or 5) after 2 cycles of chemoimmunotherapy. In total, 42 patients were enrolled of whom 40 were treated with axi-cel.

Of these patients, 37 patients were evaluable for response, with confirmed double‑ or triple-hit histology or an IPI score ≥3. After a median follow-up of 15.9 months, the complete response (CR) rate, the primary endpoint of this study, was 78%.

Secondary endpoints included objective response rate (ORR), defined as a combination of CR and partial response. ORR was achieved in 89% of the patients, with a median time to initial response of 1 month. At data cut-off, 73% of the response-evaluable patients showed ongoing responses.

Medians for duration of response (DoR), event-free survival (EFS), and progression-free survival (PFS) were not reached; 12-month estimates were 81%, 73%, and 75%, respectively. The 12-month estimated OS was 91%.

PK/PD and safety profile

Compared with the ZUMA-1 trial, the ZUMA-12 trial displayed a higher frequency of CCR7+CD45RA+ T cells in the axi-cel product. This result was associated with greater CAR T-cell expansion [6] and suggests improved T-cell fitness in first-line treatment.

The safety profile of axi-cel was manageable and comparable to previous reports [7]. All 40 treated patients had adverse events (AEs); 85% of the patients had grade ≥3 AEs, most commonly cytopenia (68%). Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in 3 patients (8%) and 9 patients (23%), respectively.

Conclusion

Axi-cel demonstrated a high rate of rapid and durable responses in the current patient population. Overall, the ZUMA-12 trial showed that axi-cel may benefit patients exposed to fewer prior therapies and those with high-risk LBCL. Further trials of axi-cel contributing to first-line therapy for high-risk patients with LBCL are warranted.

  1. Neelapu SS, et al. Primary Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) As First-Line Therapy in Patients with High-Risk Large B-Cell Lymphoma (LBCL). Abstract 739, ASH 2021 Annual Meeting, 11-14 December.
  2. Sehn LH, Salles G. N Engl J Med 2021;384:842-858.
  3. Mamot C, et al. J Clin Oncol. 2015;33:2523-9.
  4. Casasnovas RO, et al. Blood. 2017;130:1315-1326.
  5. Jacobson CA, et al. Abstract 1764, ASH 2021 Annual Meeting, 11-14 Dec.
  6. Locke FL, et al Blood advances. 2020;4(19):4898-4911.
  7. Neelapu SS, et al. N Engl J Med 2017;377:2531-2544.
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ASCT or CAR T cell as first-line therapy for MM?

Although autologous stem cell transplant (ASCT) is still the frontline therapy for patients with multiple myeloma (MM), CAR T-cell therapies have demonstrated high efficacy rates in later treatment lines, and emerging data suggest that perhaps it should be considered for earlier lines of treatment.

Prof. Salomon Manier (Lille University Hospital, France) compared the value of ASCT and CAR T-cell therapies for the treatment of patients with MM. “We do not have data from phase 3 trials comparing ASCT to CAR T-cell therapy in patients with MM,” Prof. Manier stated [1]. “Therefore, we do not yet know which is the better option. We can, however, speculate on this topic using the currently available data.”

ASCT has been shown to deliver an additional 1 to 2-year progression-free survival when added to a standard-of-care therapy [2–5]. The data does not demonstrate a benefit of ASCT on overall survival. “However, when we look at the IFM2009 trial, we can see that 76% of the patients who relapsed in the control arm received delayed ASCT, confounding the overall survival data,” added Prof. Manier [1,3]. Furthermore, additional ASCT is associated with higher minimal residual disease (MRD)-negativity rates (10-6) than the standard triple therapy of lenalidomide, bortezomib, and dexamethasone (RVd) alone (29.8% vs 20.4%; P=0.01) [3]. Similarly, higher 1-year persistent MRD-negativity rates (10-5) were reported for carfilzomib, lenalidomide, dexamethasone (KRd) plus ASCT than for KRd alone (90% vs 78%).

“What can we expect from CAR T-cell therapies in terms of MRD negativity?” asked Prof. Manier [1]. The phase 2 KarMMa trial, investigating idecabtagene vicleucel (ide-cel) in participants with MM in the late-stage setting, showed an MRD-negativity (10-5) rate of 48% for participants who were treated with the recommended dose of ide-cel [6]. Also, in the phase 1b/2 CARTITUDE-1 trial, ciltacabtagene autoleucel (cilta-cel) displayed an MRD-negativity rate of 91.8% in participants with MM who received 6 prior lines of therapy and were evaluable for MRD [7]. The MRD-negativity rate was 58% when the complete study population was considered. “Then we have the DUAL FasT CAR-T cells, targeting BCMA and CD19,” continued Prof. Manier. “A phase 2 study evaluating this option in a heavily pre-treated patient population showed that 100% of the participants who were evaluable for MRD (27 out of 28) reached MRD negativity” [1,8].

Prof. Manier commented that the results from these trials do not come from intention-to-treat populations but from patients who actually received CAR T-cell therapies. The KarMMa-3 trial (n=386) did provide results from an intention-to-treat population. The included participants had received 2 to 4 prior lines of therapy and were randomised 2:1 to ide-cel or a standard regimen, resulting in a clear progression-free survival benefit for participants who were treated with ide-cel (13.3 months vs 4.4 months; HR 0.49; P<0.0001) [9]. In total, 20% of the participants reached a complete response or better plus MRD negativity (10-5). “Furthermore, emerging data is showing that early CAR T-cell therapy is likely to result in better responses than when this type of therapy is administered in later lines,” said Prof. Manier [1,10,11].

The phase 3 CARTITUDE-6 trial (NCT05257083), comparing head-to-head in the frontline ASCT and CAR T-cell therapy following DRVd, will provide more insights. “Since a high tumour burden is a risk factor for severe cytokine release syndrome (CRS), the results of this trial may show us that frontline CAR T-cell therapy reduces the rate of severe CRS compared with administering CAR T-cell treatment in later lines of therapy,” added Prof. Manier.

  1. Manier S. CAR-T versus ASCT in Myeloma. JS03-2, European Society for Blood and Marrow Transplantation (EBMT) 49th Annual Meeting, 23–26 April 2023, Paris, France.
  2. Attal M, et al. N Engl J Med 1996;335(2):91–97.
  3. Attal M, et al. N Engl J Med 2017;376:1311–1320.
  4. Richardson PG, et al. N Engl J Med 2022;387:132–147.
  5. Gay F, et al. Lancet Oncol. 2021;22(12):1705–1720.
  6. Raje NS, et al. Abstract 635, ASH 2020, 05–08 December.
  7. Usmani SZ, et al. J. Clin. Oncol. 2021;39(15)_suppl:8005–8005.
  8. Du J, et al. Clin. Oncol. 2022; 40(16)_suppl:8005–8005.
  9. Rodríguez-Otero P, et al. N Engl J Med 2023;388:1002–1014.
  10. Cohen AD, et al. JCI. 2019;129(6):2210–2221.
  11. Garfall AL, et al. Blood Adv. 2019;3(19):2812–2815.
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Next-generation cell therapies for cancer: CAR-NK cells

Dr Katy Rezvani (MD Anderson Cancer Center, TX, USA) discussed the latest research regarding the development of CAR-natural killer (NK) cell therapies for hard-to-treat cancers. Can CAR-NK cell therapies become safe and effective off-the-shelf products?

“CAR T-cell therapies have resulted in a paradigm shift in our thinking of cancer treatment,” said Rezvani. “However, the currently available CAR T-cell therapies are all autologous and are therefore time-consuming and costly to produce.” Another issue with these therapies, according to Dr Rezvani, is limited access. To improve this situation, Dr Rezvani and co-investigators looked at the possibility of using a healthy allogeneic donor to manufacture CAR therapies and freeze doses of these cells so they can be available as an off-the-shelf product. “This would increase access and speed, and reduce costs,” added Dr Rezvani.

The general challenges to the use of allogeneic donors for CAR therapy are the risk for graft-versus-host disease, limited persistence, the choice of cell type, and the choice of donors. The research group of Dr Rezvani chose to study NK cells for this purpose. “The main advantages of NK cells over T cells in the context of allogeneic CAR therapy is that NK cells do not cause GvHD, and that NK cells attack cancer cells by means of the introduced CAR and by innate receptors, whereas T cells may cause GvHD and only have the CAR-mediated mechanism of killing cancer cells,” explained Dr Rezvani. Also, NK cells are not associated with cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). “Various allogeneic NK cell sources are being evaluated at the moment, including peripheral blood, cord blood, NK cell line, and induced pluripotent stem cells,” continued Dr Rezvani.

Dr Rezvani ‘s research focussed on cord blood. A phase 1 study that was published in 2020 demonstrated a complete response in 7 out of 11 patients with CD19-positive lymphoid tumours who were treated with CAR-transduced NK cells, without the arise of CRS, neurotoxicity, or GvHD [2]. Furthermore, CAR NK cells were detectable at 12 months post-infusion, even though the CAR NK cells were HLA-mismatched with the recipients.

Dr Rezvani’s research group is interested in the mechanisms of resistance that are associated with CAR-NK therapy. An in vivo study by Li et al. showed that CAR-NK cell trogocytosis drives relapse by downregulating target antigen on tumour cells, resulting in NK exhaustion and fratricide [3]. However, the investigators were able to demonstrate that an inhibitory CAR against an NK-specific antigen prevented fratricide and exhaustion mediated by the on-target off-tumour effect of the activating CAR.

Can CAR NK cells be applied beyond CD19-positive tumours?

Dr Rezvani then explained that the research group aimed to target non-CD19-positive tumours. “We hypothesised that pre-complexing NK cells with bispecific antibodies or FC-enhanced antibodies prior to infusion facilitates CAR-like responses by NK cells,” she said. “Pre-activation of NK cells with cytokines could potentially enhance persistence by inducing a memory phenotype,” she added. An ex-vivo study by Kerbauy et al. displayed that IL-12/15/18 pre-activated NK cells prior to expansion are associated with upregulation of genes related to the JAK-STAT pathway and interferon-γ response [4]. If these pre-activated NK cells were then loaded with a bispecific antibody, they were able to target CD16 and CD30 on cancer cells.

This concept was tested in a clinical trial (NCT04074746) in a heavily pre-treated population of 41 patients with Hodgkin lymphoma who failed on brentuximab. The 28-day response rate was 92.5%, with a 65% complete response rate. Among patients who were treated with the highest dose level of these pre-complexed NK cells, the response rate was even higher. Furthermore, no cases of CRS, ICANS, or GvHD were reported [5]. “However, the responses were transient,” added Dr Rezvani. “The results that were presented at ASH 2022 were based on a 2-cycle regimen. We need to await the follow-up responses of the 4-cycle regimen to see whether this prolonged therapy can increase the duration of responses.” She clarified that it is not surprising that the persistence of these NK cells was limited, given the short lifespan of NK cells.

Furthermore, Dr Rezvani and colleagues tested 34 different CD70 targeting CAR-NK constructs, using the extracellular domain of CD27, since CD70 is a natural ligand for CD27. The most promising CD70 CAR-NK cells displayed excellent antitumour activity and safety in mice with Burkitt lymphoma or acute myeloid leukaemia (AML). Importantly, the research group found a cryopreservation method that led to similar results for frozen CD70 CAR-NK cells as for fresh cells. Currently, 2 clinical trials are running to test IL-12/15/18 pre-activated CAR-NK cells in human populations (i.e. NCT05703854; NCT05092451).

“We need to develop CARs that target more than 1 antigen, combine CAR engineering with bispecific antibody loading, use the knowledge of cytokine engineering and CRISPR gene editing, and combine novel CAR therapies with checkpoint inhibitors, immunomodulatory drugs, and radiotherapy to begin to address the unmet need in hard-to-treat cancers such as AML and solid tumours,” Dr Rezvani concluded her presentation.

  1. Rezvani K. CAR NK cells: next-generation cell therapies for cancer. P03-01, European Society for Blood and Marrow Transplantation (EBMT) 49th Annual Meeting, 23–26 April 2023, Paris, France.
  2. Liu E, et al. N Engl J Med 2020;382:545–553.
  3. Li Y, et al. Nature Medicine. 2022;28:2133–2144.
  4. Kerbauy LN, et al. Clin Cancer Res. 2021;27(13):3744–3756.
  5. Nieto Y, et al. Abstract 168, ASH 64th Annual Meeting, 10–13 December 2022, New Orleans, LA, USA.
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Long-term success for CD19 CAR T-cell therapy in CLL

CAR T-cell therapy may be a solution for a subset of patients with heavily pre-treated, high-risk, ibrutinib-intolerant, relapsed or refractory chronic lymphocytic leukaemia (RR CLL), as shown by the 80-month follow-up results of a phase 2 trial.

“Although a [previously published] phase 1/2 trial study showed promising efficacy data of CD19 CAR T-cell therapy in patients with RR CLL, the follow-up duration of this trial was limited to 1 year,” said Dr Emily Liang (University of Washington, WA, USA) [1,2]. To assess the long-term outcomes, the participants of the current phase 2 trial were followed for a median duration of 79.6 months. The study included 55 patients with ibrutinib-intolerant RR CLL who received 1 of 3 dose levels of JCAR014 CAR T-cell therapy [2]. In total, 49 participants were infused.

The 28-day overall response rate was 70%. Similarly, 28-day minimal residual disease (MRD) negativity (10-4) was achieved by 70% of the patients. Of the patients that reached MRD negativity by flow cytometry (10-4), 62% even reached MRD negativity by next-generation sequencing (10-6).

The median duration of response was 18.9 months, and the 6-year duration of response rate was 26%. The median duration of response was significantly longer in patients who had MRD negativity (10-4) at day 28 compared with MRD-positive patients (27.1 months vs 1.8 months; Plog-rank<0.001). This difference was even larger in patients with next-generation sequencing MRD-negativity (53.4 months vs 7.8 months; Plog-rank=0.004). Finally, the 6-year progression-free survival and 6-year overall survival rates were 18% and 31%, respectively.

These findings indicate that CD19 CAR T-cell therapy could be a viable option in heavily pre-treated patients with ibrutinib-intolerant RR CLL. “After 6 years of follow-up, 6 patients remained progression-free, suggesting that CD19 CAR T-cell therapy may even be curative in a subset of patients,” Dr Liang concluded.

  1. Gauthier J, et al. Blood. 2020;135(19):1650–1660.
  2. Liang EC, et al. Factors associated with duration of response after CD19 CAR T-cell therapy for relapsed/refractory CLL: 6-year follow-up update. GS02-06, European Society for Blood and Marrow Transplantation (EBMT) 49th Annual Meeting, 23–26 April 2023, Paris, France.
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Promising phase 1 results for novel CAR T-cell therapy in MM

Anitocabtagene autoleucel (anito-cel) yielded excellent efficacy results in a heavily pre-treated population of participants with relapsed or refractory multiple myeloma (RRMM) in a phase 1 study. Phase 2 and 3 studies are initiated to further investigate this novel CAR T-cell therapy in MM.

The autologous B-cell maturation antigen (BCMA)-directed CAR T-cell therapy anito-cel was tested at 2 dose levels in a phase 1 trial among participants with RRMM who had received at least 3 prior lines of therapy. The lower dose level was administered to 32 participants, and 6 received the higher dose. Dr Binod Dhakal (Medical College of Wisconsin, WI, USA) shared findings concerning safety and efficacy [1].

The overall response rate was 100%, with a stringent complete remission (sCR)/CR rate of 76%. This result was consistent among participants with extramedullary disease (n=13) and those with high-risk cytogenetics (n=11). Dr Dhakal added that the median progression-free survival was not reached after a median follow-up of 26.5 months. The corresponding 24-month progression-free survival rate was 56%. Furthermore, 25 out of 28 evaluable participants were measurable residual disease negative (10-5). “Remarkably, these findings are consistent in participants with extramedullary disease, a feature associated with notoriously poor prognosis,” stressed Dr Dhakal.

The toxicity profile was more favourable in the lower dose group, whereas the efficacy of the lower dose appeared to be similar to the higher dose. “We did not observe any delayed neurotoxicity, Guillain-Barre syndrome, cranial nerve palsy, or Parkinsonian-like syndrome,” highlighted Dr Dhakal. Also, there were no grade 3 cytokine release syndrome cases in the low-dose group and only 1 case of grade 3 immune effector cell-associated neurotoxicity syndrome.

Altogether, anito-cel delivered encouraging results in a heavily pre-treated population of participants with RRMM in a phase 1 trial, supporting further assessment of this novel CAR T-cell therapy in RRMM.

  1. Frigault M, et al. Phase 1 study of CAR-T-ddBCMA for the treatment of patients with relapsed and/or refractory multiple myeloma: results from a least 1-year follow-up in all patients. S207, EHA congress 2024, 13–16 June, Madrid, Spain.
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