“Chronic pancreatitis can lead to cancer. So, that is a consideration for doing the auto transplant in children to avoid a problem that can develop in the future. In adults, the organs are already working sub-optimally and the cell-to-liver transplant is not the best because the liver is not the best. The general body of the recipient is not working very well.”

The pancreatic islet cell replacement therapy VX-880 reduced insulin dependence in the first 2 patients with type 1 diabetes (T1D) treated as part of a phase 1/2 study (NCT04786262).

Islet cells are emerging as a possible approach to cell therapies in such indications including T1D and chronic pancreatitis.

Recently, Alleghany Health Network performed the first islet cell transplant for the treatment of chronic pancreatitis.

The project leader is Massimo Trucco, MD, director, Alleghany Health Network Institute of Cellular Therapeutics. As part of the treatment, Trucco and colleagues remove the pancreas to eliminate the chronic pancreatitis and transplant islet cells to the liver to continue insulin production.

spoke with Trucco to learn more about the islet cell transplant procedure. He discussed eligibility and potential other applications for the transplants.

1. Markmann JF, Naji A, Rickels MR, et al. Stem cell–derived, fully differentiated islet cells for type 1 diabetes. Presented at: ADA 82nd Scientific Sessions Conference, June 6, 2022, New Orleans, Louisiana. Abstract #259-OR.
2. AHN performs its first islet cell transplants to treat chronic pancreatitis. News release. AHN. October 5, 2021. https://www.prweb.com/releases/ahn_performs_its_first_islet_cell_transplants_to_treat_chronic_pancreatitis/prweb18241294.htm

Videos

The director of the Alleghany Health Network Institute of Cellular Therapeutics discussed possible applications of the procedure. 

Massimo Trucco, MD, on the Potential of Islet Cell Transplant 

, Novartis) was shown to be both effective and well-tolerated for children expected to develop spinal muscular atrophy (SMA) type 1 or type 2, according to findings from SPR1NT (NCT03505099), a phase 3 multicenter, single-arm trial that were reported in 2 separate papers published in 

 The data were previously presented at the European Academy for Neurology Virtual Congress in 2021 and the 2022 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference.

All children in both the type 1 (2 copies of the 

) cohorts achieved the primary endpoint of independent sitting

 and nearly all children in both cohorts achieved other age-appropriate milestones including standing and walking.

 None of the children in the study required respiratory support nor nutritional support, and there were no serious treatment-related adverse events observed.

"The robust data from both the 2- and 3-copy SPR1NT cohorts are being published together for the first time, further supporting the significant and clinically meaningful benefit of Zolgensma in 

," said Shephard Mpofu, MD, SVP, chief medical officer, Novartis Gene Therapies, in a statement.

 "When treated with Zolgensma prior to the onset of symptoms, not only did all 29 patients enrolled in SPR1NT survive, but were thriving—breathing and eating on their own, with most even sitting, standing, and walking without assistance."

Of the 44 newborns screened for the SPR1NT study, 14 were excluded for reasons including clinical signs of SMA at screening or immediately before dosing (n=4), peroneal nerve to tibialis anterior CMAP <2 mV (n=4), and elevated anti-AAV9 titers (n=2).

 The type 1 cohort ultimately enrolled 14 presymptomatic infants with genetically confirmed SMA and 2 

 copies (71% female), while the type 2 cohort enrolled 15 infants (60% female) with 3 

 copies. All infants were treated with a single infusion of onasemnogene abeparvovec (median age for type 1 cohort, 21 days; median age for type 2 cohort, 32 days). Results were compared to a matched Pediatric Neuromuscular Clinical Research natural-history cohort (n = 23).

All children in both cohorts began oral prednisolone therapy 1 day prior to onasemnogene abeparvovec infusion (completing a median of 60 days for the type 1 cohort; median 63 days for the type 2 cohort).

 In all, 159 treatment-emergent adverse events (TEAEs) were observed in the type 1 cohort. However, of the 71% in this cohort who experienced a TEAE deemed related to the treatment, none were considered to be serious.

 In the type 2 cohort, 166 TEAEs were reported, with 53% of children in this cohort experiencing a TEAE deemed related to treatment, none of which were considered serious.

 A single Grade 3 hepatotoxicity event occurred in the type 2 cohort that was deemed related to treatment, but resolved with augmented prednisolone.

 Overall, the data related to adverse events from both cohorts were in line with previous data and no new safety signals were identified.

“Limitations of SPR1NT include the relatively small number of participants, the use of the PNCR external comparator group, and the exclusion of children with baseline CMAP <2 mV,” first author Kevin A. Strauss, MD, medical director, Clinic for Special Children, and colleagues noted.

Strauss and colleagues concluded that the results of this study highlight the urgency for universal newborn screening for SMA in order to allow for early identification and intervention.

“[T]reating individuals who demonstrate no symptoms of disease remains controversial,” they wrote in the paper reporting on the type 2 cohort, who typically would show symptoms by the age of 18 months. “SMA offers an example of what can be achieved when newborn screening identifies at-risk infants who can potentially be spared the consequences of severe, debilitating weakness. Children with 3 copies of 

 have a greater likelihood of developing SMA type 2 or type 3, but SPR1NT demonstrates that treating 3-copy children before the appearance of SMA symptoms essentially allows them to grow and develop as normal children. This represents a remarkable evolution in the standard of care for SMA: from a reactive to a proactive paradigm, from a focus on patients who survive to children who thrive.”

The patients enrolled in SPR1NT have since been invited to participate in a long-term follow-up study to continue to collect safety and efficacy data. Updates evaluating motor function gains are planned for publication later this year.

1. Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogeneabeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial. Nature Medicine. Published online June 17, 2022. doi10.1038/s41591-022-01866-4

2. Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogeneabeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial. Nature Medicine. Published online June 17, 2022.doi: 10.1038/s41591-022-01867-3

3. Novartis announces Nature Medicine publication of Zolgensma data demonstrating age-appropriate milestones when treating children with SMA presymptomatically. News release. Novartis. June 17, 2022. 

https://firstwordpharma.com/story/5597735

Articles

All children in the phase 3 SPR1NT study achieved the primary end point of independent sitting. 

Children Treated With Zolgensma for Presymptomatic SMA Achieve Age-Appropriate Motor Milestones

“It's like having a pipeline in a single product. So, we're able to take advantage of the biologic features of the cells, put them into multiple different indications, all with the same manufacturing processes. It's a fantastic opportunity for us because we can continue to mass produce these cells and continue to interrogate their capability across a host of different diseases.”

MiNK Therapeutics’ goal is to develop allogeneic invariant natural killer T (iNKT) cell therapies for oncologic and immune indications. iNKT cells combine the durability and memory of T-cells with the rapid killing power of NK cells.

MiNK’s lead program is AgenT-797, an off-the shelf iNKT cell therapy, in clinical trials in multiple myeloma (NCT04754100), solid tumor cancers (NCT05108623), and in patients with severe viral ARDS (NCT04582201). Initial data has demonstrated that the iNKT cell therapy has been well-tolerated when dosed up to 1 billion cells without lymphodepletion, with no incidences of cytokine release syndrome or neurotoxicity. Further data will be available in the second half of 2022.

spoke with Jennifer Buell, PhD, president and chief executive officer, MiNK Therapeutics, to learn more about the advantages of iNKT cells and the company’s CARDIS platform. She discussed data seen so far with AgenT-797.

MiNK Therapeutics announces patients dosed with AgenT-797 iNKT cell therapy in solid tumor cancers. News release. MiNK Therapeutics. March 3, 2022. https://investor.minktherapeutics.com/news-releases/news-release-details/mink-therapeutics-announces-patients-dosed-agent-797-inkt-cell

Jennifer Buell, PhD, president and chief executive officer, MiNK Therapeutics, discussed different indications for the iNKT therapy AgenT-797. 

Developing Invariant Natural Killer T Cells for Multiple Myeloma, GVHD

Adoptive cellular therapy targeting the KRAS G12D hot-spot mutation with cells engineered to express a 

 gene resulted in tumor regression in a 71-year-old patient with metastatic 

, according to findings from a case study published in 

An overall objective partial response of 62% was achieved in the regression of metastatic lung lesions at 1-month follow-up, and an overall partial response of 72% in tumor regression was achieved by the 6-month mark. Additionally, the engineered cells made up 2.4% of all circulating T cells at 6-months post-treatment.

“Although the durability of the clinical response in our patient remains to be determined, this case report shows that TCR gene therapy targeting the KRAS G12D hot-spot mutation was able to mediate the regression of metastatic pancreatic cancer” first author Rom Leidner, MD, medical director, Head & Neck Cancer Program, Providence Cancer Center and Earle A Chiles Research Institute, and colleagues wrote in a brief report.

While TCR gene therapy can target intracellular tumor-specific antigens, the investigators noted that it is dependent on the specific HLA genotype of the patient.

 Therefore, the TCR therapy used in this study, which is restricted by HLA-C*08:02, is only applicable for a low percentage of potential patients. HLA-C*08:02 is only expressed in about 11% of black persons and 8% of white persons in the United States and is expressed in even lower percentages in most other racial and ethnic groups.

“However, additional TCRs targeting KRAS G12D and other hot-spot KRAS mutants restricted by different HLA molecules that have been identified could extend TCR gene therapy against mutant KRAS to a larger number of patients,” Leidner and colleagues noted.

 “The immunologic targeting of mutant KRAS with vaccines in patients with pancreatic cancer has also been attempted, but the clinical usefulness of this approach remains unclear.”

A post-treatment biopsy to assess the tumor infiltration by the transduced T cells was not possible due to the rapidness of the tumor regression, also limiting the study.

Prior to infusion, the patient received 600 mg intravenous tocilizumab to prevent cytokine release syndrome followed by intravenous cyclophosphamide. The patient then received a single infusion of 16.2×10

 autologous T cells that had been genetically engineered to express 2 allogeneic HLA-C*08:02–restricted TCRs targeting mutant KRAS G12D. Post-infusion, the patient received intravenous high-dose interleukin-2 (600,000 IU per kilogram; one dose every 8 hours, 5 doses total) to support cell expansion.

After treatment, the patient experienced nausea and myelosuppression, which the investigators noted have been associated with cyclophosphamide preconditioning therapy. The patient also experienced hypotension during the post-treatment course of filgrastim administration. However, the investigators noted that “no toxic effects of the engineered T-cell therapy were observed.”

The investigators also mentioned a similar recent case study with less conclusive results, in which a patient with pancreatic cancer was treated under a separate single-patient investigational new drug application, with autologous T cells engineered to express the 2 HLA-C*08:02–restricted KRAS G12D–reactive TCRs. The cells were manufactured under different in vitro growth conditions without additional immune modulation with tocilizumab.

“Radiographic imaging 1 month after the infusion showed modest regression of the patient’s lung metastases and stable liver lesions. However, despite high levels of T-cell persistence in the blood, the patient had progressive disease and died 6 months after receipt of the therapy,” Leidner and colleagues noted.

The investigators concluded that prospective clinical trials are warranted to determine the therapeutic potential of this therapy in pancreatic cancer and other cancers that express KRAS G12D.

1. Leidner R, Silva NS, Huang H, et al. Neoantigen T-cell receptor gene therapy in pancreatic cancer (Research Summary). N Engl J Med.Published online June 9, 2022. doi:10.1056/NEJMoa2119662.

2. Leidner R, Silva NS, Huang H, et al. Neoantigen T-cell receptor gene therapy in pancreatic cancer. N Engl J Med. 2022;386:2112-9. doi:10.1056/NEJMoa2119662.

The treated patient achieved an overall partial response of 72% in tumor regression.

Case Study: Neoantigen TCR Gene Therapy Yields Metastatic Pancreatic Cancer Regression  

“There are resources available for Charcot-Marie-Tooth (CMT). So, if you as a physician have a patient you suspect may have CMT, there are genetic tests available. There are centers of excellence available. You can reach out to us at the CMT Research Foundation and we can help you with some of those resources. You can find us at CMTRF.org, and especially for the physician scientists who are watching today, we have dollars to support your research.”

Charcot-Marie-Tooth disease (CMT) is a rare genetic disease comprising a collection of hereditary peripheral neuropathies. Those with the different types of CMT experience a gradual weakening of their sensory and motor muscles and no disease-modifying therapies exist today for CMT.

The CMT Research Foundation (CMTRF)’s mission is to support research that may lead to cures. The CMTRF funds a number of promising projects and research in CMT, many of which are taking cell or gene therapy approaches.

spoke with Keith Fargo, PhD, chief scientific officer, CMTRF, to learn more about the CMTRF’s funded projects in the cell and gene therapy fields. He discussed promising work and partnerships, as well as resources available to those with CMT.

The chief scientific officer of the CMT Research Foundation discussed investigative cell and gene therapy approaches for treating CMT. 

Keith Fargo, PhD, on Potential Treatment Avenues for Charcot-Marie-Tooth 

The FDA has cleared the investigational new drug application (IND) for 

 ACE1831, a γδ T-cell therapy, for the potential treatment of non-Hodgkin lymphoma (NHL).

"The FDA clearance of our IND application for ACE1831 is a significant milestone for Acepodia as we move into the clinic with a first antibody armed allogeneic gamma delta T cell product candidate through our unique Antibody-Cell Conjugation (ACC) platform. Based on ACE1831's encouraging preclinical data, we believe that our antibody ­armed gamma delta T cell therapy has the potential to provide additional treatment options for patients with NHL," Sonny Hsiao, PhD, chief executive officer, Acepodia, said in a statement.

 "The ACC approach allows us to circumvent the limitations of current T cell engager therapies. Meanwhile, we can also significantly reduce manufacturing costs and have the potential to generate a cost-effective cancer treatment for patients. We look forward to advancing ACE1831 into its first clinical trial," said the chief executive officer.

ACE1831 is an allogeneic, anti-CD20 γδ T-cell therapy developed with Acepodia’s ACC platform. The therapy will be evaluated in a phase 1, first-in-human, multi-center clinical trial in patients with NHL. γδT cells

Allogeneic CAR T-Cell Therapy Yields 100% CR Rate in B-NHL

“In an in vivo model, ACE1831 showed prolonged survival compared to treatment groups utilizing the same antibody and effector cells separately. In addition, ACE1831 is shown to trigger the release of interferon gamma but not interleukin-6 while engaging target tumor cells in vivo, suggesting that ACE1831 may activate the immune system without the risk of cytokine release syndrome,” Hsiao 

Acepodia’s lead program, ACE1702, is an allogeneic, amplified natural killer (NK) cell therapy also developed with the ACC platform.

 ACE1702 is currently being evaluated in a phase 1 trial (NCT04319757) in HER2-positive tumors. 

The study is primarily evaluating safety and tolerability via the incidence and severity of adverse events (AEs) and dose-limiting toxicities as well as the maximum tolerated dose and the phase 2 recommended dose. Secondary endpoints include pharmacokinetics and pharmacodynamics such as NK cell persistence and immune function. Other outcomes evaluate preliminary efficacy by measuring tumor response via RECIST 1.1, radiographic assessments, and serum tumor marker values.

“The trial will continue to enroll patients with advanced HER2-expressing tumors. Dose escalation is continuing up to 15 billion cells per cycle with updated clinical data to be provided in the first half of 2022,” Thorsten Graef, MD, PhD, chief medical officer, Acepodia, 

1. Acepodia announces FDA clearance of IND application for ACE1831, an anti-CD20 armed allogeneic gamma delta T-cell therapy candidate to treat patients with non-Hodgkin's lymphoma. News release. Acepodia. 

https://www.prnewswire.com/news-releases/acepodia-announces-fda-clearance-of-ind-application-for-ace1831-an-anti-cd20-armed-allogeneic-gamma-delta-t-cell-therapy-candidate-to-treat-patients-with-non-hodgkins-lymphoma-301570711.html


2. Acepodia Presents Positive Interim Phase 1 Feasibility Data for Antibody Cell Effector Therapy, ACE1702, in Advanced HER2-Positive Tumors. News release. Acepodia. September 16, 2021. https://www.globenewswire.com/news-release/2021/09/16/2298101/0/en/Acepodia-Presents-Positive-Interim-Phase-1-Feasibility-Data-for-Antibody-Cell-Effector-Therapy-ACE1702-in-Advanced-HER2-Positive-Tumors.html

ACE1831 will soon be evaluated in a phase 1, first-in-human, clinical trial. 