Jasper Therapeutics and Aruvant Sciences are collaborating to study the use of JSP191, an antibody-based conditioning agent, with ARU-1801, an investigational lentiviral gene therapy for the treatment of sickle cell disease (SCD).

The goal of the collaboration is to evaluate the use of JSP191, a highly targeted anti-CD117 monoclonal antibody, as an effective and more tolerable conditioning agent that can expand the number of patients who can receive ARU-1801.

"This research collaboration with Aruvant is the first to use a clinical-stage antibody-based conditioning agent and a novel clinical-stage gene therapy, giving this combination a clear advantage by moving beyond the harsh conditioning agents currently used for gene therapy and establishing this next-generation potentially curative treatment as a leader in sickle cell disease," said Kevin N. Heller, MD, executive vice president, research and development, Jasper, in a statement. "Our goal is to establish JSP191 as a potential new standard of care conditioning agent, broadly in autologous gene therapy and allogeneic hematopoietic stem cell transplantation."

Gene therapy conditioning, used to help facilitate the engrafting of new, gene-modified stem cells, typically involves the use of high-dose chemotherapy such as busulfan, whose adverse events (AEs) may include infection, bleeding, secondary malignancy, and infertility. 

The AEs associated with gene therapy conditioning and the limited efficacy shown so far with low-dose conditioning has limited the use of hematopoietic cell transplantation despite its potential as a treatment for serious diseases. 

ARU-1801 has demonstrated durable efficacy with a lower dose of chemotherapy and a different agent with less associated AEs. The gene therapy addresses the limitations of current curative treatment options, such as low donor availability and the risk of graft-versus-host disease seen with allogeneic stem cell transplants, and unlike other approaches, requires only reduced intensity conditioning as opposed to fully myeloablative conditioning.

The ongoing phase ½ MOMENTUM study (NCT02186418) in patients with severe SCD,has demonstrated durable reductions in disease burden. The study has enrolled 10 participants and is estimated to meet primary completion in 2023, although follow-up will continue for another 13 years. Primary outcomes include incidence of grade 3 allergic reaction, grade 4 infection, grade 4 neutropenia, and grade 3 or 4 organ toxicity.

JSP191 is designed to block stem cell factor receptor signaling leading, which will clear hematopoietic stem cells from bone marrow and allow new stem cells to engraft. It is in clinical development and has been evaluated in more than 90 healthy volunteers and patients. It is currently being evaluated in 2 clinical trials for myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) and severe combined immunodeficiency (SCID). 

Jasper Therapeutics announced positive data from the phase 1 trial of JSP191 in patients with MDS/AML (NCT04429191) in February. The first 6 patients to receive a single dose of JSP191 prior to transplantation showed successful engraftment and complete donor myeloid chimerism (at least 95%) was observed in 5 patients at 28 days, and all 3 evaluated patients had total donor chimerism of at least 95% at day 90. Three of 5 evaluated patients showed complete eradication of measurable residual disease (MRD) as measured by next-generation sequencing at 28 days. Two of 5 evaluable patients showed substantial reductions in MRD. No treatment-related serious AEs were reported.

Four additional studies are expected to begin enrollment in 2021 for patients with severe autoimmune disease, SCD, chronic granulomatous disease, and Fanconi anemia undergoing hematopoietic cell transplantation.

"The unique attributes of ARU-1801 enable us to bring a potentially curative one-time therapy to individuals with sickle cell disease that can be delivered in the safest way possible," Will Chou, MD, chief executive officer, Aruvant, added to the statement. "By partnering with Jasper to evaluate the use of JSP191 with ARU-1801, we are one step closer to developing a next-generation definitive therapy with an even more patient-friendly conditioning regimen. We believe that this combination may be able to further expand the number of patients who can benefit from ARU-1801 in the future, including potentially those with more moderate disease."

REFERENCES
1. Jasper Therapeutics and Aruvant announce research collaboration to study JSP191, an antibody-based conditioning agent, with ARU-1801, a novel gene therapy for the treatment of sickle cell disease. News release. Jasper Therapeutics. June 21, 2021. 

https://www.biospace.com/article/releases/jasper-therapeutics-and-aruvant-announce-research-collaboration-to-study-jsp191-an-antibody-based-conditioning-agent-with-aru-1801-a-novel-gene-therapy-for-the-treatment-of-sickle-cell-disease/


2. Gene transfer for patients with sickle cell disease (NCT02186418). NIH US National Library of Medicine. 

https://clinicaltrials.gov/ct2/show/NCT02186418


3. Jasper Therapeutics announces positive data from phase 1 clinical trial of JSP191 as targeted stem cell conditioning agent in patients with myelodysplastic syndromes or acute myeloid leukemia undergoing hematopoietic cell transplantation. News release. Jasper Therapeutics. February 8, 2021. https://www.businesswire.com/news/home/20210208005212/en/Jasper-Therapeutics-Announces-Positive-Data-from-Phase-1-Clinical-Trial-of-JSP191-as-Targeted-Stem-Cell-Conditioning-Agent-in-Patients-with-Myelodysplastic-Syndromes-or-Acute-Myeloid-Leukemia-Undergoing-Hematopoietic-Cell-Transplantation

Articles

Jasper Therapeutics and Aruvant Sciences are studying the use of JSP191 used with ARU-1801 in patients with sickle cell disease. 

New Collaboration to Evaluate Lower-Dose Gene Therapy Conditioning for Sickle Cell Disease

This content originally appeared on our sister site

Ciltacabtagene autoleucel (cilta-cel),a CAR T-cell therapy, may compare favorably with established agents such as idecabtagene vicleucel (Abecma; ide-cel) in patients with multiple myeloma, according to C. Ola Landgren, MD, PhD.

the phase 1/2 CARTITUDE-1 trial (NCT03548207) that 

examined the BCMA-directed therapy in heavily pretreated patients with multiple myeloma were presented 

 indicated that after a median follow-up of 18 months, patients who received treatment with cilta-cel experienced an overall response rate of 97.9% with a stringent complete response (sCR) rate of 80.4%. The therapy yielded an 18-month progression-free survival rate of 66.0% in the overall patient population and was 75.9% in those who achieved a sCR.

On May 27, 2021, the FDA granted priority review status to a biologics license application for cilta-cel for the treatment of patients with relapsed/refractory disease.

 The agency is expected to make a decision on the approval by November 29, 2021.

“Cilta-cel seems to have a longer progression-free survival [PFS] than [idecabtagene vicleucel; (Abecma)], 

,” said Landgren, the inaugural leader of the Experimental Therapeutics Program at Sylvester Comprehensive Cancer Center, University of Miami. “We do not have very robust data, but the indications are that it may be a better CAR T-cell therapy. There is no randomized study to compare the two, though.”

The Institutional Perspectives in Cancer webinar on multiple myeloma covered advances across treatment settings and with immune-based therapies, utilizing genomic signatures, and getting patients to long-term sustained minimal residual disease negativity.

®, Landgren, a cochair of the webinar, focused on the cellular- and immunotherapy-based elements from the event and where these modern therapies optimally fit in multiple myeloma.

®: What were some of the most exciting trials in multiple myeloma that read out at the 2021 ASCO Annual Meeting?

 The cilta-cel results are very interesting. We now have, for the first time, a CAR T-cell therapy in myeloma that seems to deliver PFS [that is] getting close to 2 years. That is strong. I recognize that the median follow-up time is limited, and the sample size is also not very large, but it is exciting to see that it seems to last for quite a long time.

Of course, there are all these new bispecific antibodies coming. You do not have to have the procedure of being in the hospital [with bispecifics], as you have to do with the CAR T-cell therapy. You could argue that they are going to maybe challenge CAR T cells.

However, I think CAR T cells and maybe natural killer [NK] cells could be attractive for patients, because [these comprise] a single infusion. There will be openings [in the paradigm] for both cell therapy and antibody therapy. It is great for patients to have a lot of options; I am very excited about it.

Pending regulatory approvals, where could these newer modalities fit into clinical practice?

That is a question that we ask every time a new therapy is being introduced. Usually, therapies [in the first round] are being tested in later lines. That is because those patients need new therapies; [therefore,] their needs are more unmet in that space. It also takes a shorter time to develop the drugs because you get the end points faster, [therefore] it comes faster to patients.

For therapies that have been approved, the next rule is that if a therapy works reasonably well in the later-line setting, it usually works even better in an early-line setting. These are general principles, [which are] not always true, but are for the most part.

We see now that all of these therapies are moving up in earlier lines. The questions on the table when it comes to cell therapy are: “Could that challenge autologous transplants, for example, for some patients? Could it be the first relapse therapy for patients? Could it be for patients who have a [suboptimal] response in the beginning? Where is it going?” A lot of people, including us, are working on all these questions.

What data showcase the advantages of autologous and allogeneic CAR T-cell therapies?

Cilta-cel is an autologous CAR T-cell therapy that targets BCMA. [There is] ide-cel [that is approved], and orvacabtagene autoleucel [JCARH125] is in development. There are 3 of them [that] all go after BCMA [and] are autologous.

[With regard to allogeneic stem cells], from a practical point of view, an allogenic CAR T-cell therapy implies that you could give it across the board; you do not have to collect individual patients or cells. If you use an autologous CAR T-cell therapy, you have to have the patient coming in, harvest their cells, and then you have to transduce them in the lab; you have to proliferate and activate the cells and [fuse them back into the patient]. It is about 1-month turnaround time from vein to vein. [With] allogeneic [CAR T-cell therapy], you can see the patient in the clinic [and] make the decision [to give] allogeneic T cells, and the patient could be treated within 2 days or so because it is an on-the-shelf product.

The downside could be that you have to pre-medicate with certain agents to avoid graft-vs-host disease [GVHD]. Genetically, these CAR T cells have been modified, for example, to turn off CD52. Then, you can give CD52 blockers to avoid GVHD, and then you give this cell. It is a natural cell engineering and treatment premedication to avoid GVHD. It is very attractive from a feasibility standpoint; the preliminary efficacy data look very promising. However, what we do not know are the long-term effects with these types of medications to avoid GVHD. We also do not know the long-term efficacy.

Lastly, there are other new technologies in development where you could have cells that are given without a receptor to go after the tumor cells. The same cells could be used for lymphomas or solid tumors. We will see a lot of new technologies coming; it is very exciting to see how the field is accelerating forward.

Let’s focus on quality of life (QoL). How are mobile wearables being used to establish sleep bioprofiles in patients with newly diagnosed myeloma?

There are some trends that I see across the board for myeloma, from my perspective. The next focus for research in myeloma has to be on the long-term QoL, and also to make sure that we do not cause new trouble in terms of secondary malignancies with older regimens.

One interest area of mine has been to work with a team to see how we could capture QoL, [such as] activity and sleeping patterns. Neha S. Korde, MD, of Memorial Sloan Kettering Cancer Center, who I have worked with for many years, designed the study together with myself and others, and we put wearables on patients. We can see how [the effect] of therapy goes beyond the traditional responses. We see how it [affects] sleeping, how it [affects] mobility, [and if] patients are active or not.

The short summary is: We see that both younger and older patients have better mobility and better sleep quality if we use more modern therapies. We can see these in both the short and the long term. This is important to think of how we can use new technology to capture these important aspects of patients’ lives.

1. Usmani SZ, Berdeja JG, Madduri D, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapy, in relapsed/refractory multiple myeloma (R/R MM): updated results from CARTITUDE-1. 

. 2021,39(suppl 15):8005. doi:10.1200/JCO.2021.39.15_suppl.8005
2. US Food and Drug Administration grants BCMA CAR-T cilta-cel priority review for the treatment for relapsed/refractory multiple myeloma. News release. Legend Biotech Corporation. May 26, 2021. Accessed May 27, 2021. https://bwnews.pr/3fNCQK8

C. Ola Landgren, MD, PhD, discussed the role of CAR T-cell therapies in myltiple myeloma.

Car T-Cell Therapy: The Future of Multiple Myeloma Treatment?

This content originally appeared on our sister site, 

The FDA approval of the first BCMA-targeted CAR T-cell therapy idecabtagene vicleucel (ide-cel; Abecma) represents the monumental advances made in the relapsed/refractory setting, according to James E. Hoffman, MD.

FDA approved ide-cel for patients with multiple myeloma

 who had received 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. The decision was based on data from the phase 2 KarMMA trial (NCT03361748), in which the CAR T-cell product elicited an overall response rate of 72% (95% CI, 62%-81%), with a sCR of 28% (95% CI, 19%-38%) among 100 evaluable patients.

“We have been waiting for this for a long time. We have been talking about CAR T-cell therapy forever and the fact that we finally got an approval for the first commercial [product], with many centers about to be able to start [administering it], is hugely exciting,” Hoffman explained. “It is going to be looked back on a real milestone in the treatment of this disease. I hope that it sets the stage for many new CAR T-cell therapies, bispecific T-cell engagers, and other related drugs that might even be better.”

® Institutional Perspectives in Cancer webinar on multiple myeloma spotlighted advances made in frontline treatment, exciting data reported with combination regimens in the relapsed/refractory setting, progress made with immunotherapy, as well insight into the utilization of genomic signatures to define stable vs progressive precursor conditions and the evolving role of minimal residual disease (MRD).

®, Hoffman, an assistant professor of the Department of Medicine at Sylvester Comprehensive Cancer Center, discussed key developments made across the frontline and relapsed/refractory treatment settings and their clinical significance in the treatment of patients with multiple myeloma.

®: What are the key developments that have been made in the frontline treatment setting in multiple myeloma?

: [In the] up-front [setting], the primary [focus is] quadruplet or triplet [regimens]. There has been a lot of back and forth [regarding] the appropriate triplets. Bortezomib plus lenalidomide and dexamethasone and carfilzomib plus lenalidomide and dexamethasone are both reasonable options. The relative benefits between them [are often discussed] and data continue to evolve. [However], the addition of daratumumab to triplet therapy is [going to be] a very relevant hot topic moving forward.

Pivoting to the relapsed/refractory setting, what notable updates should be highlighted?

It is commonly spoken of within the field how exciting it is that we have all these novel options for [when patients] relapse; this is great for patients. Belantamab mafodotin-blmf [Blenrep], selinexor [Xpovio], CAR T-cell therapy, and melphalan flufenamide [Melflufen] are the kind of [approaches] that exist for when patients have progressed through the classic lines of therapy. In myeloma, when we talk about the anchor classes, we are talking about the proteasome inhibitors, such as bortezomib and carfilzomib; the immunomodulators, like lenalidomide and pomalidomide; and the monoclonal antibodies, like daratumumab.

When [patients] have been through those 3 classes, that is when they [pivot to these novel] agents. Each of these drugs offers a response rate and can generally be given safely. Unfortunately, the response rates [achieved with] any one of [these approaches] are not sky high. [As such, we tend to] cycle patients through [these options], and hopefully, we will find the one that works for them.

Turning to immunotherapy, the first BCMA-directed CAR T-cell therapy, ide-cel, has been FDA approved. What is the impact of this regulatory decision on the paradigm?

I sometimes talk to my patients about how it might be that this is the dial up and we are going to get to the broadband later on. Treating patients earlier [with this approach] may result in more benefit; however, is clear is that for a one-time treatment, we see a dramatic benefit in some patients—very deep responses that are somewhat durable.

Unfortunately, patients do relapse with time. This might have been somewhat a function of the fact that these are very heavily pretreated patients, on average. [Regardless], this is a monumental advance for patients with limited options; deep remissions are actually possible. Many patients are going to benefit from [this agent], and that this is a building-off point for the next year or 2, where we really hope to see an explosion of this type of treatment. We hope to potentially be able to offer [this modality] earlier in the course of disease.

How are genomic signatures being utilized to define stable vs progressive precursor diseases in myeloma?

Smoldering myeloma has really been a complicated illness. The reason for that is, you have monoclonal gammopathy of undetermined significance [MGUS], which is very benign and certainly can be observed; you have myeloma, which hurts patients and definitely [requires treatment]; and then you have patients who numerically [have] myeloma but are not sick.

The reason why that has been so challenging is, we evaluate this middle group numerically. We look at how many plasma cells are in the bone marrow, how high the abnormal antibody is, [and] how high the M-spike is. However, those are just numbers. You can have someone with high numbers [whose disease] behaves in an indolent fashion, and you can have someone with low numbers [whose disease] acts more aggressively.

The most exciting area of advancement in smoldering myeloma is [focused on] how to get at the biological underpinnings of this kind of intermediate disease and really identify biologically, who has signatures that are progressive and who has signatures that are non-progressive. By doing that, we can avoid lumping all these patients into 1 category and treating them all in the same way.

That is not a great approach because you have this category where some are going to progress, and some are not. If you give them all the same medicine, you are overtreating some and you may be undertreating others who really have myeloma. However, this approach can help us identify the progressors. As such, we can treat them [as we would] myeloma and leave the other ones alone, like we do with MGUS. I am hoping in the next year or 2, we move away from these numerical assessments, which are plagued with difficulty, and move to biologic assessments.

How is MRD currently being used in this disease and where do you see this headed?

MRD is an excellent end point. I mentioned earlier that we cannot wait around for survival data, so we look at depth of response. We have had partial responses [PRs], very good PRs, and complete responses [CRs], but by digging deep into this MRD assessment, you can find those patients who are in the deepest possible remission. It has been known for some time that the deeper the response, the better, and that MRD negativity is better than MRD positivity and MRD positivity is better than lack of CR.

The challenge, however, is [figuring out] where to incorporate that into current practice. If you have a patient who did really well, whether they are MRD positive or negative, are you going to change your approach for that patient? It is becoming clear that groups of patients who can achieve sustained MRD negativity are going to do very well. That is becoming a reasonable surrogate end point for some of these novel and aggressive therapies.

It is probably, true to a degree, that getting to sustained MRD negativity is far more important than how you got there. Whether you needed transplant to get there or whether you needed a quadruplet regimen, getting there is what really matters. Certainly, as it relates to clinical trials, MRD has become an acceptable end point. In terms of common practice, it is not there yet because we really do not know what to do with the information. However, all the forward-thinking approaches are utilizing MRD negativity, and I do not see that changing.

1. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. 

. 2020;136(8):936-945. doi:10.1182/blood.2020005288
2. US Food and Drug Administration approves Bristol Myers Squibb’s and bluebird bio’s Abecma (idecabtagene vicleucel), the first anti-BCMA CAR T cell therapy for relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb and bluebird bio. March 26, 2021. Accessed June 16, 2021. 

James Hoffman, MD, discussed the significance of the approval of ide-cel for patients with multiple myeloma.

The Potential of CAR T-Cell Therapy for Multiple Myeloma 

While progress is being made in multiple myeloma treatments and strategies, unmet needs remain for patients with high-risk disease, poor prognostic factors, and relapsed disease.

“Things are changing in multiple myeloma, and it is definitely becoming more of a chronic disease. However, there are certain patient groups that we need to pay particular attention to, and those would be the high-risk patients that still have a poor survival,” said Faith E. Davies, MD, a professor in the Department of Medicine and director of the Clinical Myeloma Program at NYU Langone Health’s Perlmutter Cancer Center. “Also, we need to learn how to embrace many of the new therapies that are being developed, and particularly, learn how to manage their adverse effects [AEs] so that we can better utilize them with our patients.”

The 2021 Institutional Perspectives in Cancer webinar on multiple myeloma focused on up-front and relapsed/refractory updates in the disease, as well as how to approach patients with high-risk myeloma. In an interview with 

®, Davies discussed the latter, as well as how CAR T-cell therapies fit best for that patient population.

: There are several therapeutic options for patients with relapsed/refractory myeloma. How do you choose what is best for someone with early relapsed disease?

When we are thinking about treating patients with early relapsed multiple myeloma, we need to [consider] a whole host of factors. The first one would be how well [the patient] did with their initial therapy and exactly what that treatment was, so that we can decide whether we need to stay with the same class of drugs or change it. We also need to think about the adverse effects [AEs] that the patient may have [experienced] with their initial therapy so that we can ideally try to avoid those AEs moving forward.

Finally, we need to think about comorbidities, because many patients may have aged a little since we started their initial therapy, and therefore, we need to think [more] about cardiac and neuropathy issues, diabetes, etc., so we can get a handle on which drug classes we should be including in our combinations.

One of the talks during the program focused on CAR T-cell therapy in patients with multiple myeloma. What promise has this modality demonstrated in the early relapse setting?

For CAR T cells, most of the studies have been performed in patients with relapsed/refractory disease. The data in that patient group—where in the past we have always been surprised if patients have a response or if they have a long remission—have shown that there is a high response rate, that there is a high number of patients achieving minimal residual disease negativity, and that many of those patients can have a prolonged disease-free period.

[There are] certainly a number of AEs associated with [CAR T-cell] therapy, which need some management, but it shows a lot of promise. The promise may actually be earlier in the disease course, because if you think that the kinds of results we are seeing in patients who have previously had 10 lines of therapy, imagine what kind of results we might get in patients who are at their first relapse, for instance. Many of the clinical studies that are being undertaken now are looking at [CAR T-cell therapy in] earlier lines of therapy, or indeed, looking at those high-risk patients who may be in their first line of therapy. We are looking to see whether CAR T-cell therapy may be appropriate for them.

Faith E. Davies, MD, discussed the potential of CAR T-cell therapies for the treatment of multiple myeloma.

CAR T-Cell Therapy for Early-Relapsed Multiple Myeloma

After longer follow-up, ciltacabtagene autoleucel (cilta-cel) led to early, deep, and durable responses in patients with relapsed/refractory multiple myeloma (MM) with a manageable safety profile, according to updated results from the ciltacabtagene autoleucel CARTITUDE-1 trial (NCT03548207) presented at the 2021 European Hematology Association (EHA) Congress.

At the meeting, Saad Z. Usmani, MD, FACP, director of the Plasma Cell Disorder Program and director of clinical research in hematologic malignancies at Atrium Health, presented updated results from the phase 1b/2 trial with a median follow-up of 18 months.

Overall response rate (ORR) was 97.9%, including a 94.8% very good partial response (VGPR) or better. Moreover, the stringent complete response (sCR) rate was 80.4% and the partial response rate (PR) was 3.1%.

The median time to first response was 1 month (range, 0.9–10.7), with a time to best response of 2.6 months (range, 0.9-15.2). The median time to complete response or better (≥CR) was 2.6 months (range, 0.9-15.2). Duration of response was 21.8 months (95% CI, 21.8–not estimable [NE]), and median duration of response had not been reached in patients with sCR. The investigators estimated that 73% of responders had not progressed or died at 12 months.

Moreover, response rates were comparable across subgroups (range, 95%–100%), including number of prior lines of therapy, refractoriness, extramedullary plasmacytomas, and cytogenetic risk.

Of the 61 evaluable patients for minimal residual disease (MRD), 91.8% achieved MRD negativity at the 10-5 threshold, including 89.4% with ≥CR, compared with 57.7% and 43.3% of all patients, respectively. Median time to MRD negativity at 10-5 was 1 month (range, 0.8-7.7).

Among all patients, the 18-month progression-free survival (PFS) rate was 66.0% (95% CI, 54.9%-75.0%), and 75.9% (95% CI, 63.6%-84.5%) in those with sCR. Median PFS among all patients was 22.8 month (95% CI, 22.8 to NE) and was not reached in those with sCR.

Lastly, the 18-month overall survival (OS) rate in all patients was 80.9% (95% CI, 71.4%-87.6%).

The investigators did not identify any new safety signals with longer follow-up.

Cytokine release syndrome (CRS) occurred in 92 patients, of which the majority (94.6%) were grade 1/2 in severity. The median time to onset of CRS was 7 days (range, 1-12); however, the events resolved in 91 patients (98.9%) within 14 days of onset.

In addition, there was no new incidence of neurotoxicity with longer follow-up, and no additional movement and neurocognitive treatment-emergent adverse events (TRAEs).

No patient discontinued therapy due to manufacturing failure, while 1 patient received retreatment with cilta-cel.

In total, 21 patients died during the study, of which 10 were due to progressive disease, 6 from TRAEs as assessed by the study investigator, and 5 were from AEs unrelated to treatment.

Usmani noted that new patient management strategies have been implemented in the trial to prevent and reduce the incidence of neurotoxicity, including enhanced bridging therapy to reduce tumor burden, early and aggressive treatment of CRS and immune effector cell–associated neurotoxicity syndrome, and handwriting assessments and extended monitoring.

“Patient management strategies to prevent or reduce these AEs have been successfully implemented in new and ongoing cilta-cel studies,” the investigators wrote. “This is reliant on effective implementation of these patient management strategies.”

The study was designed to evaluate cilta-cel, a chimeric antigen receptor (CAR) T-cell therapy with 2 B-cell maturation antigen (BCMA)–targeting single-domain antibodies, in patients with relapsed/refractory MM who have been heavily pretreated.

Patients received a single cilta-cel infusion with a target dose of 0.75 × 106 CAR-positive viable T cells/kg and a median dose of 0.71 × 106 CAR-positive viable T cells/kg (range, 0.5–1.0 × 106 CAR+ viable T cells/kg) 5 to 7 days after lymphodepletion with 300 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine daily for 3 days. Bridging therapy was permitted after apheresis.

The primary aims of the study were to evaluate safety, confirm the recommended phase 2 dose (RP2D), and evaluate efficacy.

Key eligibility criteria for patients included progressive MM per International Myeloma Working Group (IMWG) criteria; receipt of 3 or more prior therapies or double refractory disease to a proteasome inhibitor (PI) plus immunomodulatory drug (IMiD) and a PI, IMiD, and an anti-CD38 antibody therapy; measurable disease; and an ECOG performance status ≤1.

Of the 97 patients who received cilta-cel infusion, 76 were ongoing at the time of the data cut-off. In total, 73 patients received bridging therapy between apheresis and cilta-cel infusion.

The median time from receipt to release of product for cilta-cel was 29 days (range, 23-64).

Patients had a media age of 61 years (range, 43-78). The majority were male (58.8%). Patients had received a median of 6 prior lines of therapy (range, 3-18), with 87.6% who were triple-class refractory and 42.3% who were penta-drug refractory. Lastly, 99% of patients were refractory to their last line of therapy.

In a previous analysis at 12.4 months of follow-up, the ORR was 97%, with an sCR of 67%. In addition, 12-month PFS and OS were 77% and 89%, respectively.

Cilta-cel is being investigated in the ongoing phase 2 CARTITUDE-2 (NCT04133636) and phase 3 CARTITUDE-4 (NCT04181827) studies in earlier-line settings.

Usmani S, Berdeja J, Madduri D, et al. UPDATED CARTITUDE-1 RESULTS OF CILTACABTAGENE AUTOLEUCEL, A B-CELL MATURATION ANTIGEN–DIRECTED CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY, IN RELAPSED/REFRACTORY MULTIPLE MYELOMA. Presented at: 2021 European Hematology Association Annual Meeting; June 9-17, 2021; Virtual; Abstract EP964.

At the 18-month follow-up, the CAR T-cell therapy led to early, deep, and durable responses with a manageable safety profile in patients with relapsed/refractory multiple myeloma.

Longer Follow-Up Shows Cilta-Cel Induces Deep, Durable Responses in Relapsed/Refractory MM

Weak cell specification and required high dosing are just some of the limitations of current capsids used for gene therapy approaches. As the potential for gene therapy is realized in a broader set of disorders, the need for more specific capsids will increase. 

 is tackling this challenge with their novel capsid discovery platform, SAVVY,  that they are developing in partnership with the Children's Medical Research Institute in Australia. In addition, the company is working with multiple partners to develop novel therapies for several indications using SAVVY and their proprietary gene editing technology, GeneRide. 

The company recently announced that the first patient has been dosed with LB-001 in the phase 1/2 SUNRISE trial (NCT04581785) for methlymalonic acidemia (MMA), which utilizes the GeneRide technology platform. The technology removes the need for exogenous nucleases and promoters associated with an increased risk of immune response and cancer. LB-001 is designed to insert a functioning copy of MMUT to the albumin locus to achieve sufficient, lifelong MMUT expression in the liver via engineered recombinant adeno-associated virus vectors (rAAV-LK03).

To learn more about the platforms and therapeutic targets they could serve, 

 spoke with LogicBio chief scientific officer, Mariana Nacht, PhD. 

Videos

LogicBio's Mariana Nacht, PhD, shares details of the company's novel capsid discovery platform and gene editing technology. 