"The patient experience is quite different when patients go to transplant: the length of hospitalization, the immediate complications, and the follow ups, which are longer after transplant, and more intense. While, with the gene therapy protocol, a lot of it is avoided just by the absence of all the immunosuppressive and myeloablative agents that we have to give them.”

The gene therapy RP-L102(Rocket Pharma) demonstrated phenotypic correction, including increased resistance to mitomycin-C in bone marrow-derived colony forming cells, concomitant genetic correction and hematologic stabilization in at least 6 of 10 participants with Fanconi anemia with a trend of improvement in a seventh participant, meeting the primary endpoint of its phase 2 study (NCT04069533).

RP-L102 had a favorable safety profile, although 1 participant did experience a grade 2 transient infusion-related reaction, determined to be unrelated to treatment, which resolved. Based on the positive data, Rocket plans to complete regulatory filings for the therapy in the second half of 2023.

 spoke with Rajni Agarwal-Hashmi, MD, professor of pediatrics, stem cell transplantation, Stanford Cancer Institute, to learn more about the trial and the recent data presented on RP-L102. She also stressed the advantages of gene therapy over traditional stem cell transplant treatment, especially with regards to safety and the lack of myeloablative conditioning in the treatment course.

Rocket Pharmaceuticals presents positive clinical data from fanconi anemia, pyruvate kinase deficiency and severe leukocyte adhesion deficiency-I programs at the 64th American Society of Hematology (ASH) Annual Meeting. News release. Rocket Pharmaceuticals. December 12, 2022. https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-presents-positive-clinical-data-fanconi-0

Videos

The professor of pediatrics at Stanford Cancer Institute discussed recent data from clinical trials of the lentiviral gene therapy RP-L102. 

Rajni Agarwal-Hashmi, MD, on Safety Advantages of Gene Therapy in Fanconi Anemia Over SOC 

The Israeli Ministry of Health (IMOH) has cleared a phase 1/2 clinical trial (NCT05581719) investigating Enlivex’s Allocetra cell therapy for the treatment of solid tumors for continuation, following a positive review from an independent data and safety monitoring board (DSMB) of data from the first cohort.

Allocetra is an investigational allogeneic cell therapy intended to reprogram macrophages that have become "pro-tumor" tumor associated macrophages (TAMs) back into a homeostatic state.

 It is comprised of non-HLA matched peripheral blood mononuclear cells derived from a healthy human donor that have been induced into an apoptotic stable state. The clinical trial’s first cohort treated 3 patients with Allocetra as monotherapy.

 Allocetra was administered either intravenously (IV) or intraperitoneally (IP), depending on tumor location, in 3 once-weekly doses. At 21 days of follow-up from the first dose, there were no deaths or safety signals identified by the DSMB for the 3 treated patients. The DSMB recommended that the trial continue without modifications to its design. In light of the data, the IMOH provided regulatory clearance for Enlivex to begin recruiting patients for the trial’s next 2 cohorts, which will treat patients with higher doses of Allocetra. In 1 of these cohorts, patients will receive Allocetra as a monotherapy, while in the other cohort, patients will receive Allocetra in combination with the anti-PD1 immune checkpoint inhibitor nivolumab.

"We are pleased with the safety profile of Allocetra as demonstrated in the first 3 patients in this trial,” Oren Hershkovitz, PhD, chief executive officer, Enlivex, said in a statement regarding the news.

 “We look forward to initiating the next 2 cohorts in which higher doses of Allocetra will be administered in patients, allowing Enlivex to obtain additional safety data as well as a potential indication of effect."

In total, the multicenter, open-label, dose escalation trial is anticipated to enroll approximately 48 patients aged 18 years and older who have advanced, unresectable or metastatic solid tumors. Patients are required to have relapsed or been refractory to available approved therapies, or to be ineligible for or declined treatment with additional standard of care systemic therapy. Patients with peritoneal carcinomatosis may be included if an appropriate IP catheter or port is placeable. Patients are additionally required to have measurable disease, an Eastern Cooperative Oncology Group score of 1 or lower, and adequate renal, hepatic, and bone marrow function. Patients with clinically unstable primary central nervous system (CNS) malignancy or CNS involvement; clinically significant uncontrolled infection; autoimmune or inflammatory diseases requiring systemic immunosuppression; clinically significant cardiovascular disease; severe pulmonary diseases; or additional malignancies will be excluded from participation. Participants in the trial’s second stage, which will treat patients with the combination therapy approach, must additionally not have previously had an immune checkpoint inhibitor (ICI)-related adverse reaction that resulted in discontinuation of the ICI.

The study’s primary end point is safety based on dose-limiting toxicities. Secondary end points include the overall response rate (ORR) and best ORR, clinical benefit rate, duration of response, time to response, progression-free survival, and overall survival. Changes in immune cell and cytokine profiling in the peritoneal fluid will also be evaluated. The trial is recruiting at several centers in Israel and is estimated to be completed in June 2024.

originally cleared the trial for initiation

 Allocetra had previously demonstrated potential in preclinical research. In an ovarian cancer mouse model, mice treated with Allocetra in combination with an anti-PD1 checkpoint inhibitor showed an 83% increase in survival duration compared to an untreated group.

 Additionally, the combination therapy group had a survival probability up to 50%, compared to 0% in the untreated group. In addition to solid tumors, Allocetra is also being evaluated for the treatment of patients with peritoneal metastasis (NCT05431907), patients with COVID-19 (NCT04659304, NCT04922957), 

1. Enlivex announces positive DSMB recommendation and IMOH clearance to continue phase I/II trial of Allocetra in patients with advanced solid tumors. News release. Enlivex Therapeutics Ltd. Janaury 25, 2023. Accessed Janaury 25, 2023. 

https://finance.yahoo.com/news/enlivex-announces-positive-dsmb-recommendation-133700145.html

2. Enlivex receives Israeli Ministry of Health approval for the initiation of a phase I/II trial evaluating Allocetra alone and in combination with a PD1 checkpoint inhibitor in patients with advanced solid tumors. News release. Enlivex Therapeutics Ltd. August 17, 2022. 

https://www.globenewswire.com/news-release/2022/08/17/2499939/0/en/Enlivex-Receives-Israeli-Ministry-of-Health-Approval-for-the-Initiation-of-a-Phase-I-II-Trial-Evaluating-Allocetra-Alone-and-in-Combination-with-a-PD1-Checkpoint-Inhibitor-in-Patie.html

3. Enlivex announces new preclinical data in ovarian cancer showing a substantial survival benefit when Allocetra is combined with PD-1 checkpoint inhibition at the American Society of Clinical Oncology (ASCO) annual meeting. News release. Enlivex Therapeutics Ltd. May 31, 2022. 

https://www.globenewswire.com/en/news-release/2022/05/31/2453221/0/en/Enlivex-Announces-New-Preclinical-Data-in-Ovarian-Cancer-Showing-a-Substantial-Survival-Benefit-when-Allocetra-is-Combined-with-PD-1-Checkpoint-Inhibition-at-the-American-Society-o.html

Articles

There were no deaths or safety signals identified by the DSMB for the 3 treated patients in cohort 1.

Solid Tumor Cell Therapy Combination Trial Cleared to Continue

The FDA has cleared Sana Biotechnology’s investigational new drug application (IND) for SC291, a CD19-targeted 

 chimeric antigen receptor (CAR) T-cell therapy for the potential treatment of various B-cell malignancies.

“The clearance of our SC291 IND is an important milestone, putting us closer to our goal of making an important medicine for patients with B-cell lymphomas and leukemias,” Steve Harr, President and chief executive officer, Sana Biotech, said in a statement.

 “We look forward to understanding the safety, potency, and persistence of these cells in patients, and we are optimistic that SC291 can become an important medicine for patients with these difficult cancers. Furthermore, this platform forms the backbone for additional development of CAR T cells targeting CD22, BCMA, and beyond. We expect initial clinical data from the SC291 study later this year and believe insights from this study will better inform our opportunities across the broader platform, both for CAR T cells and for programs outside of cancer such as our pancreatic islet cell therapy for patients with type 1 diabetes.”

SC291 is developed with the use of Sana Biotechnology’s hypoimmune platform that is designed to address immunologic rejection of allogeneic cells with the body, and Sana believes the platform could yield longer CAR T persistence and higher, more durable complete response rates in B-cell lymphomas and leukemias. The platform addresses rejection by disrupting major histocompatibility (MHC) class I and MHC class II expression to hide cells from the adaptive antibody and T cell responses. The platform also overexpresses CD47 to inhibit activation of innate immune responses with macrophages and natural killer cells. Preclinical studies of the platform have demonstrated its ability to cloak cells from immune recognition, meanwhile, preclinical studies of SC291 have supported its potential as a therapy for B-cell malignancies.

Alan Trounson, PhD, MSc, on New Frontiers in Allogeneic Cell Therapy

Sana Biotechnology also revealed plans to submit another IND for SC262, a CD22-targeted allogeneic CAR T therapy also developed with the hypoimmune platform for the same potential indications of SC291, B-cell malignancies including non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL). Sana is also developing cell therapies for multiple myeloma, diabetes, central nervous system diseases, and hemoglobinopathies.

“We are making significant progress with our platforms to address two of the fundamental opportunities to enable greater utilization of cell engineering to treat serious diseases – overcoming immune rejection of allogeneic cells and in vivo delivery of gene modification reagents in a cell-specific manner. We look forward to generating human proof of concept starting next year and are positioning the company to invest fully based upon the clinical data,” Harr said in a previous statement.

1. Sana Biotechnology announces FDA clearance of investigational new drug application for SC291, a hypoimmune-modified, CD19-targeted allogeneic CAR T therapy for patients with B-cell malignancies. News release. Sana Biotechnology. January 26, 2023. 

https://www.globenewswire.com/news-release/2023/01/26/2596469/0/en/Sana-Biotechnology-Announces-FDA-Clearance-of-Investigational-New-Drug-Application-for-SC291-a-Hypoimmune-modified-CD19-targeted-Allogeneic-CAR-T-Therapy-for-Patients-with-B-Cell-M.html


2. Sana Biotechnology confirms key program timelines and announces portfolio prioritization. News release. November 29, 2022. https://ir.sana.com/news-releases/news-release-details/sana-biotechnology-confirms-key-program-timelines-and-announces

Sana Biotechnology also plans to submit another IND for the same indications for a CD22-targeted CAR T later in 2022. 

Allogeneic CAR T Cleared for B-cell Malignancy Trials 

Orbsen Therapeutics’ ORBCEL, an investigational allogeneic bone marrow-derived mesenchymal stromal cell (MSC) therapy being evaluated in the phase 1/2a NEPHSTROM clinical trial (NCT02585622) for the treatment of progressive diabetic kidney disease (DKD) in adults with type 2 

 (T2D), has generated promising safety and efficacy data in interim results from the study’s first cohort.

ORBCEL consists of highly purified immunomodulatory stromal cells and is administered intravenously. The first cohort treated 12 participants with ORBCEL at a dose of 80x10

 cells and 4 participants with a placebo (Cryostor CS10). It was noted that the safety and tolerability profile was similar for both the ORBCEL and placebo cohorts, with no adverse events (AEs) related to the infusions of stromal cells reported. In terms of efficacy, serum creatinine-based estimated glomerular filtration rate (CKD-EPI, 

 = 0.034) measurements indicated a statistically significant association between ORBCEL treatment and preservation of kidney function over baseline during the study's 18 month duration, in comparison to the treatment with the placebo. Furthermore, it was noted that, based on monitored blood markers, evidence of stabilization in the proportion of regulatory T-cells in the blood was associated with treatment with ORBCEL, while a tendency for a decrease in the proportion of regulatory T-cells in the blood was observed in patients who received the placebo.

"The current standard of care for DKD patients includes multiple types of drug therapy, such as renin-angiotensin-aldosterone system inhibitors and the more recently approved drug class known as sodium-glucose transporter 2 (SGLT2) inhibitors, which have a proven ability to slow the decline of kidney function,” Guiseppe Remuzzi, director, Mario Negri Institute for Pharmacological Research IRCCS, Bergamo, Italy, said in a statement regarding the news. “However, these medication classes are not tolerated by all patients and are not always effective to fully halt or reverse the progression of kidney injury in DKD. ORBCEL cell therapy might be particularly useful as an additional treatment in patients with rapidly progressive kidney disease caused by diabetes."

The multicenter, double-blind NEPHSTROM study is enrolling patients aged at least 40 years and less than 85 years who have had T2D for at least 3 years. Participants are additionally required to have a urinary albumin excretion of at least 60 µg/min, a urine albumin-to-creatinine ratio of at least 88 mg/g, an estimated GFR (eGFR) of 30 to 50 ml/min/1.73 m

 by the CKD-EPI equation on 2 or more consecutive measurements at least 30 days apart within the previous 6 months, and a documented decline of eGFR of at least -10ml/min/1.73 m

 over the past 3 years or a documented rate of eGFR decline of at least -5 ml/min/1.73 m

per year based on 3 or more consecutive readings at least 90 days apart in the previous 18 months. Participants must also not have a suspected 

 diagnosis other than DKD. Patients with a current resting systolic blood pressure (BP) of 150 mmHg or greater and a current resting diastolic BP greater than or equal to 90 mmHg in a clinical setting, even with treatment with 3 hypertensive agents of different classes; patients who began treatment with a new anti-hypertensive agent, a new lipid lowering agent, or a new hypoglycemic agent within the past 6 months; patients who increased their dose of an anti-hypertensive agent by 100% or more of the previous dose within the previous 3 months; patients with a current HbA1c greater than 75 mmol/mol, a current fasting total cholesterol more than 7 mmol/l, or current fasting total triglycerides more than 3.5 mmol/l will be excluded from participation. Patients who screen positive for clinically significant anti-HLA antibodies will also be excluded. Additional exclusion criteria relate to patient health status, health history, and treatment history.

The study’s primary end point is the number and severity of all pre-specified infusion-associated events and the overall number and frequency of adverse events. Among the study’s numerous secondary end points are measures of GFR, Urinary Albumin/Creatinine Ratio, Urinary albumin excretion, and fasting blood glucose. The study is taking place at locations in Ireland, Italy, and the United Kingdom.

Orbsen Therapeutics has announced its intention to submit the results from the first cohort to a peer-reviewed journal for publication. The company also noted that the trial’s second cohort, which will treat 13 patients, either at a dose of 160x10

 cells or with the placebo, completed enrollment in late 2022, and interim data from this cohort is anticipated in the second half of 2023. A phase 2b study for ORBCEL is also in the planning stage, with the company seeking communication with regulatory agencies regarding trial design.

"We're very encouraged by the safety profile and the preliminary efficacy signal that we have seen with our allogeneic cell therapy in patients with diabetes and chronic kidney disease,” Stephen Elliman, chief scientific officer, Orbsen Therapeutics, added to the statement. “Our goal with ORBCEL is to resolve systemic inflammation and improve kidney function, so that these patients will not require dialysis or a kidney transplant. The growing burden of DKD and its impact on healthcare make this an important disease target for Orbsen and our technology."

Orbsen Therapeutics announces encouraging interim results from the NEPHSTROM proof of concept clinical study evaluating ORBCEL cell therapy in patients with diabetes and advanced chronic kidney disease. News release. Orbsen Therapeutics Limited. January 26, 2023. Accessed January 27, 2023. 

https://finance.yahoo.com/news/orbsen-therapeutics-announces-encouraging-interim-090000140.html

No adverse events related to the infusions of stromal cells were reported.

MSC Therapy Shows Promise in Diabetic Kidney Disease

Carina Biotech has received a “Safe to Proceed” letter for its investigational new drug application (IND) for its LGR5-targeted chimeric antigen receptor (CAR) T-cell therapy CNA3103 to be evaluated in a phase 1/2 trial in participants with 

“Our positive engagement with the FDA marks a major step forward for Carina and our continued efforts to develop CNA3103 as a potential treatment for the third most common cancer in the U.S. and worldwide, colorectal cancer,” Deborah Rathjen, chief executive officer, Carina Biotech, said in a statement. “The FDA’s letter provides the pathway for this clinical trial and further validates that a significant unmet need exists for more effective treatment options for colorectal cancer. Preparations, including site selection, are underway as we aim to commence enrolling patients during the first half of 2023.”

Carina is on track to commence patient enrollment in the study in the first half of 2023. The trial has a target enrollment of 44 participants with metastatic, advanced, LGR5-expressing colorectal cancer that has failed prior lines of chemotherapy. The phase 1 portion of the study will enroll 24 patients in select Australian centers, and, in a Bayesian Optimal Interval design will administer ascending CAR-T cell doses to cohorts of 3 patients each. The trial will assess the safety and tolerability of CNA3103 and determine the recommended phase 2 dose. The phase 2 portion of the study will enroll 20 more patients at the optimal dose in both Australia and the US and evaluate antitumor activity, duration of response, and time to disease progression in patients treated with CNA3103.

Diane Simeone, MD, on Addressing Unmet Needs in Colorectal Cancer, NSCLC, and Pancreatic Cancer

CNA3103 targets LGR5, a cancer stem cell gene highly expressed on advanced colorectal cancer and other cancers, with a particularly poor prognosis associated with LGR5-expressing colorectal cancer. Carina hopes that the therapy’s targeting of cancer stem cells will suppress tumor growth and prevent relapses. Preclinical studies of CNA3103 have demonstrated complete tumor regression without recurrence after a single administration, with exceptional tumor access and prolonged survival.

“This interaction with the FDA corroborates our ability to gain the agency’s support for our proposed trial of CNA3103 in metastatic colorectal cancer patients,” José Iglesias, MD, chief medical officer, Carina Biotech, added to the statement. “Our approach is doubly innovative, in being one of the of emergent CAR-T treatment protocols in solid tumors and in utilizing a novel, and to our knowledge, unique CAR-T construct against LGR5 – an important cancer stem cell-associated antigen linked to the pathogenesis, dissemination, and treatment resistance of colorectal cancer.”

Carina Biotech receives FDA “Safe to Proceed” letter for IND application for phase 1/2a clinical trial of LGR5-targeted CAR-T cell therapy candidate for treatment of advanced colorectal cancer. News release. Carina Biotech. January 24, 2023. https://www.carinabiotech.com/3324-2/

The phase 1 portion of the trial assessing CNA3103 will start enrollment in Australia in the first half of 2023; the phase 2 portion will expand to the US. 

Advanced Colorectal Cancer CAR T Cleared for Trial

Experts provide their perspective on the treatment landscape for patients with relapsed-refractory (R/R) large B-cell lymphoma (LBCL).