News in Cell and Gene Therapy for Rare Cancer Day 2024

According to the National Organization for Rare Disorders, more than 1 out of every 4 cancer diagnoses are for rare cancers and 25% of all deaths from cancer are attributed to rare cancers. Despite these numbers, funding for research for individual rare cancer types tends to be low and great unmet need remains for many patients with these diseases.

In light of Rare Cancer Day, held annually on September 30 by the patient and clinician communities, CGTLive® has taken a look back at the past few months of news on cell and gene therapies in rare cancer, in order to offer a snapshot of the therapeutic progress being made in this field.

Vironexis Biotherapeutics’ AAV Vector-Based Immunotherapy VNX-101 Cleared for US Trial in Acute Lymphoblastic Leukemia

September 17, 2024 — Vironexis Biotherapeutics has received clearance of its investigational new drug (IND) application from the FDA for VNX-101, an adeno-associated virus (AAV) vector-based gene therapy, enabling a phase 1/2 clinical trial in CD19+ acute lymphoblastic leukemia.

VNX-101 is intended to transduce cells of the liver, causing them to express a transgene coding for a bispecific T-cell engager. This T-cell engager, which binds to CD19 on tumor cells and CD3 on T-cells, is intended to facilitate the targeted killing of the cancer cells by endogenous T-cells. It is based on the company’s TransJoin platform, which it is also working on applying to a variety other cancers through different investigational products; these other therapeutic candidates currently remain in preclinical development. The announcement of the IND clearance also coincides with the company’s exit from stealth, and follows a $26 million round of seed financing.

“We’re excited to launch Vironexis from stealth and reveal our noteworthy progress advancing AAV-delivered T-cell immunotherapy,” Samit Varma, the cofounder and chief executive officer of Vironexis, said in a statement. “Our novel technology builds on the power of T-cell immunotherapy while overcoming key shortcomings and challenges of existing approaches such as chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies. We believe we have the opportunity to dramatically improve upon the safety, efficacy and durability of these drug classes, while streamlining manufacturing and significantly lessening the burden of treatment for patients. Our focus on execution has yielded an expansive pipeline and a clinic-ready lead program in just 3 years. We’re working as quickly as possible to transform the future of cancer treatments for patients.”

CARsgen Finishes Enrolling Patients in Pivotal Trial in China for Gastric/Gastroesophageal CAR-T Satri-Cel

August 23, 2024 — CARsgen has completed the enrollment of patients in its pivotal phase 2 clinical trial (NCT04581473) evaluating satricabtagene autoleucel (satri-cel; CT041), an investigational chimeric antigen receptor T-cell (CAR-T) therapy that targets CLDN18.2, for the treatment of CLDN18.2-positive advanced gastric/gastroesophageal (GC/GEJ) cancer.

The open-label, multicenter, and randomized trial, which is taking place in China, is assessing satri-cel against a control group, in which patients will be treated with either paclitaxel, docetaxel, irinotecan, apatinib, or nivolumab, according to the judgement of the treating physician. The study was open to patients with advanced GC/GEJ whose disease was not successfully treated with 2 or more previous lines of therapy.

“We are very pleased to announce the successful completion of patient enrollment in the pivotal phase 2 clinical trial of satri-cel in China,” Zonghai Li, MD, PhD, the founder, chairman of the board, CEO, and chief scientific officer of CARsgen Therapeutics, said in a statement. “This significant milestone marks another solid step forward in our development of CAR T-cell therapies for solid tumors. We extend our gratitude to all the investigators, the patients and their families for their trust and support. We look forward to the submission of a New Drug Application and the approval in China, to benefit patients with gastric cancer. As one of the leading companies in the field of CAR T-cell therapies, we remain committed to addressing the major challenges faced by existing CAR T-cell therapies and will develop more innovative CAR-T products for cancer patients.”

FDA Approves Adaptimmune’s TCR T-cell Therapy Afami-cel for Synovial Sarcoma

August 2, 2024 — The FDA has granted accelerated approval to Adaptimmune Therapeutics’ afamitresgene autoleucel (afami-cel, formerly ADP-A2M4), an investigational T-cell receptor (TCR) T-cell therapy marketed as Tecelra, for the treatment of synovial sarcoma (SS). It is the first engineered T-cell therapy to be approved by the FDA for a solid tumor indication, indicated specifically for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA antigen(s) A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive, and whose tumor expresses the MAGE-A4 antigen as determined by FDA authorized companion diagnostic devices.

“Potentially life-threatening cancers such as SS continue to have a devastating impact on individuals, especially those for whom standard treatments have limited efficacy due to tumor growth and progression,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in a statement. “The approval of this state-of-the-art immunotherapy technology provides a critical new option for a patient population in need and demonstrates the FDA’s dedication to the advancement of beneficial cancer treatments.”

Sandra D’Angelo, MD, Sarcoma Medical Oncologist and Cell Therapist, Memorial Sloan Kettering Cancer Center, and the SPEARHEAD clinical trial's principal investigator, noted that the therapy "uses each patient’s own immune cells to recognize and attack their cancer cells in a one-time infusion treatment" and "is significantly different than the current standards of care for advanced synovial sarcoma." She added that the FDA decision "represents a much-needed new option for people diagnosed with this sarcoma and an important milestone for the use of cell therapies in solid tumor cancers.”

Mustang Bio’s CAR-T MB-106 Achieves Responses in 9 of 10 Patients With Waldenstrom Macroglobulinemia

June 18, 2024 — Mustang Bio’s and Fred Hutchinson Cancer Center (Fred Hutch)’s MB-106, an investigational CD20-directed autologous CAR T-cell therapy being evaluated in a single-center phase 1/2 clinical trial (NCT03277729) at Fred Hutch, demonstrated an overall response rate of 90% in the trial’s Waldenstrom macroglobulinemia (WM) cohort, which treated 10 patients in total. The data were presented at the European Hematology Association (EHA) 2024 Congress, held June 13 to 16, both virtually and in Madrid, Spain.

The responses seen in the 9 patients included 3 complete responses (CRs), 2 very good partial responses, and 4 partial responses. The patient who did not respond showed stable disease. Mustang highlighted that 1 of the patients who achieved a CR has maintained their remission for 31 months and also pointed out that this patient had shown a rapid reduction in immunoglobulin M to the normal range, where it has since remained, after being treated with the CAR-T. The company noted that 1 of the patients has begun receiving another antiWM treatment after having received MB-106. It also stated that the trial allowed for outpatient treatment and that it had demonstrated feasibility in this regard.

In terms of safety, 9 of the 10 patients experienced cases of cytokine release syndrome ranging from grade 1 (n = 5) to grade 2 (n = 4) in severity. Immune effector cell-associated neurotoxicity syndrome occurred in only 1 patient, and the case was considered grade 1.

Enhanced Lymphodepletion Regimen Improves ORR in Patients Receiving Wugen’s CAR-T WU-CART-007 for T-Cell Malignancy

June 15, 2024 — Wugen’s WU-CART-007, an investigational allogeneic CD7-directed CAR-T therapy intended to treat r/r T-cell acute lymphoblastic leukemia (T-ALL) and r/r T-cell lymphoblastic lymphoma (T-LBL), has demonstrated improved overall response rates (ORR) in patients who received an enhanced lymphodepletion (eLD) regimen prior to treatment as opposed to a standard lymphodepletion (sLD) regimen. The data comes from a phase 1/2 clinical trial (NCT04984356) and were presented at the European Hematology Association (EHA) 2024 Congress, held June 13 to 16, both virtually and in Madrid, Spain.

Thirteen of the 28 patients treated in the study received the eLD regimen, which consisted of 30 mg/m2/day of fludarabine administered at Days –6, -5, -4, and –3 and 1000 mg/m2/day of cyclophosphamide at Days –5, -4, and –3. All patients who received the eLD regimen were treated with 900x10⁶ cells of WU-CART-007, which constituted dose level 4 (DL4) in the study and the recommended phase 2 dose. For 11 of these 13 patients who were evaluated for ORR, the ORR was 91% (10/11). In comparison, 3 patients who had received the sLD regimen, which consisted of 30 mg/m2/day of fludarabine administered at days -5, -4, and –3 and 500 mg/m2/day of cyclophosphamide at days –5, -4, and –3, and were treated with WU-CART-007 at DL4, the ORR was 66% (2/3). First author Ouiam Bakkacha, MD, and colleagues, also pointed out that among patients treated at DL4, expansion and persistence of the CAR T-cells were increased in patients who had received the eLD in comparison to the patients who had received the sLD. Results for best mean percent change in bone marrow blasts also indicated better antileukemic activity in patients who had received the eLD.

REFERENCES
1. Celebrate Rare Cancer Day with NORD. National Organization for Rare Disorders (NORD) website. Accessed September 30, 2024. https://rarediseases.org/get-involved/rare-cancer-day/