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spoke with Nina Shah, MD, hematologist/oncologist and associate professor of medicine, University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, about the current state of cellular therapy in multiple myeloma.

Shah discussed the expansion of cell therapies in the field of multiple myeloma with multiple therapies,  including autologous BCMA-directed CAR T-cell therapies. Data with the FDA-approved product idecabtagene vicleucel (Abecma) showed that one dose of therapy can induce long remissions in patients with heavily pretreated disease. Additionally, ciltacabtagene autoleucel was granted priority review designation by the FDA for the treatment of patients with relapsed/refractory multiple myeloma.

However, a shortcoming of CAR T-cell therapy in multiple myeloma is that there is not yet a plateau on the survival curves, which means that the disease remains incurable, Shah continues. Although patients may derive a treatment-free interval of 1 year, they will eventually progress and require additional therapy. As such, novel cellular therapies are needed to improve the durability, accessibility, and persistence of T-cells for patients, Shah concludes.

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The hematologist and oncologist from University of California, San Francisco discussed the current state of cellular therapy in multiple myeloma.

State of Cell Therapy in Multiple Myeloma: Nina Shah, MD

MD Anderson Cancer Center has announced that they are now offering caspase-9 (CaspaCIDe®), an inducible safety switch, as well as related technologies, and rimiducid for the use of patients receiving 

. The new offerings are a product of MD Anderson's license agreement with Bellicum Pharmaceuticals.

CaspaCIDe, which contains a CID-binding domain connected to the caspase-9 signaling domain, is activated with an infusion of rimiducid, causing selective apoptosis of the CaspaCIDe-containing cells. The safety switch is designed to address common adverse events (AEs) such as cytokine release syndrome (CRS) and neurotoxicity, and is still useful long after the initiation of a cellular therapy.

“The unique inducible caspase-9 technology covered by this agreement has the potential to reduce the risk of serious adverse events associated with cellular therapies and to improve patient outcomes,” said Katy Rezvani, MD, PhD, professor of Stem Cell Transplantation and Cellular Therapy at MD Anderson, in a press release. “We have successfully applied the technology to existing cell therapies, and we look forward to the potential future applications made possible by this agreement.”

Research shows that adoptive cell therapies (ACTs) lead to AEs that are more prevalent than AEs associated with radiation and chemotherapy, and the AEs from cellular therapies can last for several years. CRS, the most common toxicity, is observed with all ACTs and typically manifests as fever and chills to start. Immunosuppressive agents like glucocorticoids and anti-IL-6/IL-6 receptor antibodies are used to treat CRS, however experts still consider this AE to be a challenge in patients with cancer.

Recognizing and Managing AEs in CAR T-Cell Therapy

The use of chimeric antigen receptor (CAR) T-cell therapies, T-cell receptor engineering therapies (TCR-T) and tumor-infiltrating lymphocyte (TIL) therapy can cause neurotoxicity, which has clinical characteristics like confusion, delirium, expressive aphasia, obtundation, myoclonus, and seizure. This toxicity can be concurrent with CRS, making for a bigger treatment challenge. Other AEs related to the use of cellular therapies include off-target associated with both CAR T-cell therapy, and high dose IL-2–related toxicity associated with TILs.

In studies, the CaspaCIDe safety switch has demonstrated improvement of symptoms within rimiducid 24 hours. There are 45 clinical trials ongoing at MD Anderson that may be impacted by this license agreement. Currently, MD Anderson is the site for 12 clinical trials of chimeric antigen receptor T-cell therapies, 5 trials of T-cell receptor engineering therapies, 5 studies of tumor-infiltrating lymphocytes, and 23 trial of natural killer cell therapies.

“We are excited to expand our CaspaCIDe agreement with MD Anderson to include a broader set of programs to benefit cancer patients,” said Rick Fair, president and CEO of Bellicum Pharmaceuticals, in the press release. “We believe that our switch technology may enhance the benefit/risk profile of cell therapies. We intend to continue to pursue opportunities to expand its use via external collaborations with other leaders in the field.”

1. MD Anderson and Bellicum announce additional license agreement for use of CaspaCIDe® safety switch. News release. MD Anderson Cancer Center. September 1, 2021. Accessed September 3, 2021.

2. Jin Y, Dong Y, Zhang J, et al. The toxicity of cell therapy: Mechanism, manifestations, and challenges.

. 2021;41(5):659-667. doi: 10.1002/jat.4100

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The new technologies were made available as a result of the licensing agreement between MD Anderson and Bellicum Pharmaceuticals.

MD Anderson to Offer Solutions to Cell Therapy AEs

OpRegen, a cell therapy from Lineage Cell Therapeutics, 

, with demonstrated anatomical and functional improvements in geographic atrophy (GA) in dry age-related macular degeneration (AMD), according to updated interim results from its ongoing phase 1/2a clinical study (NCT02286089).

Lineage announced the data in support of the investigative therapy’s efficacy, including an average difference in Best Corrected Visual Acuity (BCVA) of over 2 ETDRS lines (10.8 letters read) between treated and untreated eyes in a cohort of patients 9 to 12 months after treatment.

“OpRegen is the only investigational therapy which has shown evidence of retinal restoration. All other approaches in clinical development are directed toward slowing the expansion of the area of atrophy and cannot reverse it,” Brian Culley, chief executive officer, Lineage Cell Therapeutics, told 

OpRegen, an allogeneic retinal pigment epithelium (RPE) cell therapy, is currently being evaluated in the phase 1/2 open-label, dose escalation study which is assessing the safety and efficacy of a single injection of the therapy to the subretinal space, with a primary outcome of incidence and frequency of treatment-emergent adverse events (TEAEs). Secondary outcomes are assessing changes in ophthalmological parameters.

Challenging Paradigms in AMD: Gregory S. Hageman, PhD

Twenty-four patients have been enrolled in 4 cohorts, the first 3 of which enrolled participants with BCVA of 20/200 or worse. The fourth cohort enrolled 12 participants with BCVA from 20/65 to 20/250 with smaller mean areas of GA and also investigated a new “thaw-and-inject” formulation of OpRegen.

“Even in patients with an incomplete coverage of OpRegen over the primary area of atrophy, we have observed resolution of not only lesions of iRORA (incomplete retinal pigment epithelial and outer retinal atrophy), but also resolution of areas with features of cRORA, which is a state of complete loss of the RPE and outer retinal tissue. Additionally, the structural benefits may help explain the improvement in visual acuity. I eagerly look forward to new data as they are collected,” Jordi Monés, MD, PhD, director, Institut de la Màcula and Barcelona Macula Foundation, said in a statement.

Safety results are in line with previous data, with no new, unexpected ocular or systemic AEs or serious AEs. The updated results now include a minimum of 9 months follow-up in all 12 patients of Cohort 4. Eight of 12 treated eyes in this cohort improved in BCVA, compared with 9 of 12 (75%) untreated eyes which worsened in BCVA. There was an average difference of 10.8 letters between treated and untreated eyes at last assessment.

Previous improvements in retinal structure and drusen density, as well as a trend toward slower GA progression in treated eyes compared to untreated eyes continue to remain, and evidence of durable engraftment the RPE cells has extended to more than 5 years in the earliest treated patients.

“There is nothing approved in dry AMD. Notably, the leading approaches have not shown any improvement to visual acuity. OpRegen may be able to address not only the underlying anatomical problem, but also provide improved visual acuity, all with one-time dosing,” Culley told 

Data from ongoing clinical trial continues to demonstrate a single administration of OpRegen® can provide anatomical and functional improvements in patients with dry AMD with geographic atrophy. News release. Lineage Cell Therapeutics. September 15, 2021. https://www.businesswire.com/news/home/20210915005401/en/Data-From-Ongoing-Clinical-Trial-Continues-to-Demonstrate-a-Single-Administration-of-OpRegen%C2%AE-Can-Provide-Anatomical-and-Functional-Improvements-in-Patients-With-Dry-AMD-With-Geographic-Atrophy

Lineage Cell Therapeutics announced promising data from interim results of the phase 1/2a clinical trial assessing the cell therapy.

OpRegen Continues to Show Efficacy in Dry AMD Geographic Atrophy

This content is originally from our sister site, 

spoke with Larry Anderson, MD, PhD, associate professor, department of internal medicine, division of hematology/oncology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, about data from the phase 2 KarMMa trial (NCT03361748). 

He discussed outcomes with idecabtagene vicleucel (ide-cel, Abecma) in patients with relapsed/refractory multiple myeloma seen in the trial. Updated results from the trial were presented at the 2021 

 and showed that ide-cel yielded a median overall survival (OS) of 24.8 months in heavily pretreated patients with triple-class exposed relapsed/refractory multiple myeloma.

Overall survival was similar for those who had received 3 or more prior lines of therapy, Anderson explains. Additionally, the median OS was more than 20 months for patients with extramedullary and triple-class refractory disease.

The CAR T-cell therapy elicited an overall response rate (ORR) of 73% and resulted in a median progression-free survival (PFS) of 8.6 months, Anderson explains. Notably, in the subset of patients who received the highest dose of CAR T cells, the ORR was even higher, at 81%, with a complete response (CR)rate of 39%. In this subset, the median PFS was 12.2 months, Anderson says.

Notably, responses to ide-cel were durable, with a median duration of response of 10.9 months among all treated patients. The durability increased with depth of response, to 21.5 months of remission for those who achieved a CR and 41% of these patients were still in remission 2 years later, Anderson concludes.

The associate professor from the Harold C. Simmons Comprehensive Cancer Center of UT Southwestern Medical Center discussed the latest data from the KarMMA trial.

Updated KarMMA Data of Ide-Cel in Multiple Myeloma: Larry D. Anderson Jr, MD, PhD

 Weekly Rewind! We’ve compiled 5 highlights from this week’s coverage of advances in gene and cell therapies, including FDA actions, notable research, and interviews with experts across the field.

Addressing Exhausted T-Cells in CAR T Therapy: Joseph A. Fraietta, PhD

The director of the Solid Tumor Immunotherapy Lab at the University of Pennsylvania discussed the issue of exhausted T-cells, touching on the role of BET proteins in T-cell function and their mechanism of exhaustion.

Astellas Pauses Gene Therapy Trial for X-Linked Myotubular Myopathy

Following Astellas Pharma’s voluntary pause of their ASPIRO trial due to a patient experiencing a serious liver AE, the trial has now been placed on a second clinical hold after the patient died. This marks the fourth death over the course of the trial.

Elucidating the Role of HTRA1 in Developing AMD: Gregory S. Hageman, PhD; Brandi L. Williams, PhD

Directors from the Moran Eye Center discussed their research on the genetics of age-related macular degeneration, including the mechanism of AMD and their discovery of the protective effect of the HTRA1 gene.

T Cell Therapy Trial for High-Risk Patients With COVID-19 Now Enrolling

Tevogen Bio and Thomas Jefferson University are beginning enrollment of their phase 1 trial of TVGN-489 for the treatment of high-risk patients with COVID-19, which could potentially be the first cell therapy treatment for the virus.

Paul Lammers, MD, MSc, the president and chief executive officer of Triumvira Immunologics, discussed the company’s T-cell antigen coupler technology, its potential in both hematologic malignancies and solid tumors, and their investigations in their lead program, TAC-01 HER2.

Review top news and interview highlights from the week ending September 17, 2021. 

GeneTherapyLive’s Weekly Rewind – September 17, 2021 

 from the phase 3 SALAMANDER trial (NCT03174522) of REX-001 has demonstrated sufficient safety and efficacy in patients with critical limb-threatening ischemia (CTLI) for the trial to continue, Ixaka announced.

While the unblinded data has not yet been released, the trial’s independent Data Monitoring Committee (DMC) has assessed the interim data from the first 30% of enrolled patients 12 months after treatment and has stated that the trial has met prespecified safety and efficacy checkpoints. 

“We are delighted with the positive outcome in this interim analysis of the Phase 3 trial for REX-001 in CLTI. With such poor treatment options available and the high number of patients affected, this is a significant milestone in this devastating disease. The positive interim analysis confirms the potential of REX-001 as an effective treatment of the disease”, Joe Dupere, chief executive officer, Ixaka, said in a statement.

REX-001 is an investigative, autologous, multi-cell therapy designed to treat CLTI in patients with diabetes. It is designed to address the underlying processes such as plaque deposition, inflammation, ischemia, vessel degeneration, and ulcer formation that lead to clinical progression in CLTI. Ixaka, formerly Rexgenero, believes that the therapy could meet a high unmet need in this therapeutic space as REX-001 is currently the furthest advanced product in this indication. 

CLBS12 Granted Orphan Designation for Thromboangiitis Obliterans

“This first Phase 3 interim analysis is a critical milestone for our lead cell therapy candidate REX-001. The positive benefit-risk evaluation by the DMC provides reassurance that REX-001 is an effective and safe treatment for CLTI, and that it is on the right path towards marketing authorization,” Gilbert Wagener, MD, senior vice president and chief medical officer, Ixaka, added to the statement.

The DMC stated that the interim data from the randomized, double-blind, placebo-controlled, adaptive SALAMANDER trial shows efficacy in line with previously clinical trials. The preceding phase 2 clinical trial (NCT03111238) demonstrated that REX-001 treatment resulted in complete ulcer healing in 75% of patients compared to 14% of patients in the control group. They observed no significant safety concerns. 

“Based on these results, I am confident that we can provide our innovative and much-needed product to patients suffering from CLTI in the near future,” Wagener added.

SALAMANDER is enrolling patients with diabetes and Rutherford category 5 CLTI. The trial’s primary endpoint is complete ulcer healing or change in Rutherford classification from Category 5 to Category 4 or lower 12 months after treatment. It is recruiting in sites across Europe, including the UK, Spain, Austria, Portugal, Poland, Hungary, the Netherlands, the Czech Republic, Latvia, Lithuania and Georgia.

The interim analysis is 1 of 2 planned, the second of which will occur when 50% of patients enrolled have reached the 12-month follow-up visit. Over 50% of patients have been treated so far. No unblinded data will be released until the trial’s completion, which is set for the end of April 2022.

Ixaka announces positive interim Phase 3 clinical trial data for its lead cell therapy candidate REX-001. News release. Ixaka. September 8, 2021. https://www.ixaka.com/news/ixaka-announces-positive-interim-phase-3-clinical-trial-data-for-its-lead-cell-therapy-candidate-rex-001/

An interim analysis has met prespecified safety and efficacy checkpoints. 