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European Society for Medical Oncology Congress (ESMO)

"The most valuable advantage we see so far would be the safety profile associated with HER2-TAC T-cells and it is very well differentiated thus far compared to approved CARs. So far we have not seen any dose limiting toxicities, cytokine release syndrome, or neurotoxicity in dose levels 1 and 2."

Triumvira Immunologics’ TAC01-HER2, a HER2-targeted T-cell antigen coupler (TAC) T-cell therapy, was well-tolerated with early signs of clinical activity. In new data from cohort 2 of the phase 1/2 TACTIC-2 study, the therapy yielded a partial response in a patient with stage 4b gastric cancer and a 75% disease control rate.

Data from the study were presented by Benjamin L. Schlechter, MD, instructor, medicine, Harvard Medical School, and Dana-Farber Cancer Institute, at the 

European Society for Medical Oncology (ESMO) Congress 2022

, held September 9-13, in Paris, France. The trial will be enrolling in its phase 2 portion in the beginning of 2023.

 spoke with senior author Deyaa Adib, MD, chief medical officer, Triumvira Immunologics, to learn more about unmet needs in patients with solid tumors. He discussed the advantages of the TAC T-cell technology in addressing these unmet needs, including a positive safety profile with lower rates of cytokine release syndrome compared to those seen in other cell therapy trials.

Click here to read more coverage of ESMO Congress 2022.

Schlechter BL, Ileana Dumbrava EE, Olson D, et al. A phase I/II trial investigating safety and efficacy of autologous TAC T-cells targeting HER2 in relapsed or refractory solid tumors. Presented at: ESMO Congress 2022, September 9-13, Paris, France. Poster #778TiP

The chief medical officer of Triumvira Immunologics discussed how TAC01-HER2 could address unmet needs in treating solid tumors. 

Deyaa Adib, MD, on Safety Advantages of TAC T-Cell Therapy in Solid Tumors 

“There used to be a paucity of industry interested in NK cell biology and now that's exploded. Now, everybody's interested in autologous NK cells or induced pluripotent stem cells-derived NK cells.”

Natural killer (NK) cell approaches are being investigated more and more for treating both hematologic malignancies and solid tumors. Presentations on new NK cell approaches were given at the 

European Society of Medical Oncology (ESMO) Congress 2022

, held September 9-13, in Paris, France. One such presentation was given by Jeffrey Miller, MD, professor and deputy director of the Masonic Cancer Center of the University of Minnesota, on GTB-5550, a B7H3 tri-specific killer engager (TriKE) that specifically stimulated expansion of natural killer (NK) cells in preclinical models of multiple cancers.

The novel dual camelid (cam) TriKE contains wild type interleukin-15 and 2 cam engagers that target CD16 on NK cells and B7H3 on multiple solid tumors. The data presented demonstrated GTB-5550'sability to increase activity of NK cells against cancer cells after stimulation.

 spoke with Miller to learn more about NK cell research and other promising approaches discussed at the ESMO Congress. He touched on new avenues of research including NK cell combinations with PD1 blockades and different platforms to produce NK cells.

Miler JS, Zorko N, Merino A, et al. B7H3-targeted tri-specific killer engagers deliver IL-15 to NK cells but not T-cells, and specifically target solid tumors as a pan-tumor antigen strategy mediated through NK cells. Presented at: ESMO Congress 2022, September 9-13, Paris, France.

The deputy director of the Masonic Cancer Center discussed trends of presentations from ESMO 2022. 

Jeffrey Miller, MD, on Emerging Research With Natural Killer Cells 

“As of August, we have completed dose levels 1 and 2, in the escalation component of our phase 1 trial. We’ve seen a very pleasant surprise, a partial response in a patient who has stage 4b gastric cancer at the second dose level, which is still a very low dose level. This patient has metastatic disease, and essentially had passed 2 prior treatment lines, including HER2-targeted therapies.”

TAC01-HER2 (Triumvira Immunologics), a HER2-targeted T-cell antigen coupler (TAC) T-cell therapy, was well-tolerated and demonstrated early signs of clinical activity, including a partial response in a patient with stage 4b gastric cancer and a 75% disease control rate in cohort 2.

These data, from the phase 1/2 TACTIC-2 study, were presented at the 

, held September 9-13, in Paris, France, by Benjamin L. Schlechter, MD, instructor, medicine, Harvard Medical School, and Dana-Farber Cancer Institute.

spoke with Deyaa Adib, MD, chief medical officer, Triumvira Immunologics, and senior author of the poster to learn more about the study and its recent updates. He discussed the trial’s progress so far and the cases of stable disease and partial response. The trial will be enrolling in its phase 2 portion in the beginning of 2023.

The chief medical officer of Triumvira Immunologics discussed updates from the TACTIC-2 study presented at ESMO Congress 2022. 

Deyaa Adib, MD, on Evaluating HER2 TAC T-Cell Therapy in Solid Tumors 

“We learned [in a previous study] that the immune engager to the NK cell is critically important. And while that study was ongoing, we discovered that if we took a nanobody, single domain antibody to engage CD16, we had significantly greater potency. So that's really the premise for putting this together.”

GTB-5550, a B7H3 tri-specific killer engager (TriKE) specifically stimulated expansion of natural killer (NK) cells in preclinical models of multiple cancers. These data were presented at the 

, held September 9-13, in Paris, France, by Jeffrey Miller, MD, professor and deputy director of the Masonic Cancer Center of the University of Minnesota.

GTB-5550 is a novel dual camelid (cam) TriKE that contains wild type interleukin-15 as well as 2 cam engagers to target CD16 on NK cells and B7H3 on multiple solid tumors. Miller and colleagues demonstrated increased activity of NK cells against cancer cells after stimulation with the TriKE engager.

spoke with Miller to learn more about the study’s results and the importance of improving targeting and engagement of NK cells with antibodies. He also discussed the potential for a clinical trial in the near future investigating the approach.

The deputy director of the Masonic Cancer Center discussed the preclinical findings of his study on a TriKE engager and NK cells. 

Jeffrey Miller, MD, on Engaging NK Cells in Solid Tumors 

“I’m excited about cellular therapy in general in solid tumors... I am really optimistic because I do think that, like in hematologic malignancies, such as lymphoma, it's just a matter of time before we kind of tweaked the technology to have higher efficacy and longer efficacy in these patients who after standard chemo really have no other options.”

Patients with metastatic ovarian, urothelial, gastroesophageal, and head and neck cancers remain without many options when early lines of treatment are not successful. T-cell receptor (TCR) engineered T-cell therapy is being explored as a potential option to address this unmet medical need.

David S. Hong, MD, professor and deputy chair, department of investigational cancer therapeutics, MD Anderson Cancer Center, The University of Texas, recently 

presented data from the phase 1 SURPASS clinical trial

 (NCT04044859), which is investigating ADP-A2M4CD8, a CD8+ TCR T-cell therapy, at the 

2022 European Society for Medical Oncology (ESMO) Congress, September 9-13, in Paris, France

, Hong explained how ADP-A2M4CD8 functions and gave an overview of the study’s findings so far. He also discussed the limitations of the trial and potential avenues for future research. In particular, he mentioned future plans to investigate the therapy in combination with checkpoint inhibitors, and additionally pointed out the need to further investigate means of identifying which patients can benefit from TCR T-cell therapy. He also expressed optimism about the future of cell therapy for the treatment of solid tumors in general.

Hong presented data from the SURPASS clinical trial at the 2022 European Society for Medical Oncology (ESMO) Congress.

David S. Hong, MD, on the SURPASS Clinical Trial and TCR T-cell Therapy in Solid Tumors 

“Our principle using the bridging drug is only to stabilize. We do not hope to choose a very effective method to make our patient better... in fact, we cannot do that because in the cell therapy stage we definitely have no very good choice.”

European Society for Medical Oncology (ESMO) 2022 Congress

, September 9-13, 2022, in Paris, France, Weijia Fang, MD, Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, presented data from a phase 1 clinical trial (NCT05028933) for 

, an investigational chimeric antigen receptor (CAR) T-cell therapy which targets the EpCAM protein. The ongoing clinical trial is treating patients with advanced gastric and colorectal cancers who have no standard treatment options remaining.

, Fang commented on a limitation of the clinical trial’s design that was pointed out by Alessandra Curioni, MD, Center of Hematology and Oncology, University Hospital Zurich, during an invited discussion of the study presentation at ESMO. The limitation related to the use of a bridging chemotherapy before the administration of IMC001.

Guoqiang Ai, MD, Immunofoco Biotech Co., also joined the interview to expand on future plans for the clinical trial, describing the planned second stage, which will combine IMC001 with radiofrequency or microwave ablation therapy. Fang rounded out the interview by discussing potential future research into methods of determining which patients can benefit most from cell therapies, mentioning liquid biopsy as an area of interest.

Fang commented on a limitation of the clinical trial pointed out at the European Society for Medical Oncology (ESMO) 2022 Congress. 

Weijia Fang, MD, and Guoqiang Ai, MD, on the Future of IMC001 in Gastric and Colorectal Cancer

“The emphasis I will place is, first, we have 8 patients now, 4 with gastric cancer and 4 with colorectal cancer. The second point is that we have no dose limiting toxicities observed.”

Gastrointestinal cancers remain a leading cause of cancer-related deaths in China, and for patients with advanced colorectal and gastric cancers, treatment options are limited.

, Weijia Fang, MD, Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, and Tianhang Luo, MD, Gastrointestinal Surgery Department, Shanghai Changhai Hospital, discussed unmet needs for patients with advanced colorectal and gastric cancers and IMC001, an investigational chimeric antigen receptor (CAR) T-cell therapy which targets the EpCAM protein. Fang recently discussed the ongoing phase 1 clinical trial (NCT05028933) for IMC001 in a 

presentation at the European Society for Medical Oncology (ESMO) 2022 Congress

, September 9-13, 2022, in Paris, France.

Fang explained the key findings that have come out of the clinical trial so far, discussing the safety profile and pointing out that no dose-limiting toxicities have been observed so far. Luo discussed potential advantages of IMC001 compared with current standards of care, noting that cytoreductive surgery has been an ineffective treatment for patients with advanced gastric cancers with metastasis.

Fang recently presented at the European Society for Medical Oncology (ESMO) 2022 Congress.

Weijia Fang, MD, and Tianhang Luo, MD, on EpCAM-Targeted CAR-T Therapy in Advanced Colorectal and Gastric Cancer 

MT026, an IL13Rα2-targeted universal chimeric antigen receptor T-cell (UCAR-T cell) therapy, was well-tolerated and demonstrated anti-tumor activity in 

These data, from a single-center, first-in-human, investigator-initiated trial in China, were presented at the 

, taking place September 9-13 in Paris, France, by Yulun Huang, MD, professor, department of neurosurgery, Dushu Lake Hospital and Soochow University, Suzhou, China.

“Glioblastoma is the most common intracranial malignant tumors, which is difficult to treat and has poor prognosis,” Huang and colleagues wrote.

Huang and colleagues treated 6 patients with recurrent glioma with MT026 as of July 2022. These patients had a median age of 52 years and 4 were female. They mostly had medium IL13Rα2 expression.

SNK01/Checkpoint Inhibitor Combo Yields Sustained Remission in Advanced SRC Sarcoma Case

Cells expanded well and persisted for over 30 days. Investigators noted an expansion-correlated response in study participants, all but 1 of which responded. Response also seemed correlated to IL13Rα2 tumor expression.

“Use of autologous T cell immunotherapy for treatment of high-grade glioma… is limited. Off-the-shelf allogeneic universal CAR-T cells have unique advantages and clinical potential for those tumors which tissues are hard to collect and progress rapidly,” Huang and colleagues wrote.

Common adverse events (AEs) included fever and hypoxia. Most AEs that occurred in more than 1 participant were grade 1 or 2 except for 1 case of grade 3 hypoxia. There were no cases of severe cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Elevated interleukin-6 (IL-6) levels in the cerebrospinal fluid were the most common abnormal lab finding but IL-6 blood concentrations were low after administration.

Patients responded to MT026, with 1 complete response, 4 partial responses, and 1 case of stable disease for an overall response rate of 83.3% and a disease control rate of 100%. Survival data were favorable compared to the normal disease course, with patients having a mean overall survival of 9.8 (max, 17.5) and a mean progression-free survival rate of 5.0 (max, 7.9). Patients had a 66.7% 12-month survival rate after recurrence compared to 15% in history data. Similarly, mean survival duration after recurrence was 15.2 months (max, 33.4) compared to less than 9 months in history data.

“Intra-lumbar injection of IL13Ra2 UCAR-T cells is safe and well tolerated in humans, and IL13Ra2 UCAR-T cells have potent anti-tumor activity for recurrent high-grade glioma. Off-the-shelf allogeneic universal CAR-T therapy is a potential option for treatment of solid malignancies with rapid progression and difficulty collecting tissues,” Huang and colleagues concluded.

Huang Y, Shang X, Li X. The clinical results of an investigator initiated trial of allogeneic CAR-T cells targeting IL13Rα2 in the treatment of high-grade glioma. Presented at: ESMO Congress 2022, September 9-13, Paris, France. Poster #300P.

MT026 had an overall response rate of 83.3% in a first-in-human, investigator-initiated trial.

IL13Rα2 Universal CAR T Therapy Shows Antitumor Activity in Recurrent Glioma

The natural killer (NK) cell therapy SNK01 appears to be safe with some evidence of clinical activity when combined with checkpoint inhibitors (CI) in patients with 

These data, from 8 patients for which the FDA authorized compassionate use of the therapy, were presented at the

 European Society for Medical Oncology (ESMO) Congress 2022

, September 9-13, in Paris, France, by Victoria S. Chua, MD, director, clinical research, Sarcoma Oncology Center.

“For patients with advanced sarcomas in the relapsed/refractory setting, few effective treatment options exist. The likelihood of response or tumor control diminishes with each subsequent line of therapy,” Chua and colleagues wrote. “Monotherapy of PD-L1 inhibitors has shown modest to no activity in sarcomas, especially in tumors with low or no PD-L1 expression. NK cells have been implicated in the antitumor response to immune CI with evidence suggesting a role in PD-L1-negative tumors."

SNK01 is a first-in-kind, autologous, non-genetically modified NK cell therapy. It is designed to have enhanced cytotoxicity and an over 90% activating receptor expression to allow it to be consistently produced from heavily pretreated patients.

TCR T-Cell Therapy Shows Efficacy Across MAGE-A4+ Solid Tumors

The patients had a median age of 58.8 years (range, 16-75), a median of 4.5 lines of prior therapy (range, 3-10), and 5 were male. Sarcomas were all stage 4 and types were chondrosarcoma, small round cell sarcoma (SRCS), leiomyosarcoma, pleomorphic sarcoma, uterine sarcoma, osteosarcoma, mucinous adenocarcinoma, and a sarcoma not otherwise specified (NOS).

All 8 patients received their first immune checkpoint inhibitor (ICI) dose but only 5 were able to receive the ICI and SNK01 combination dose. Patients received 200 mg of pembrolizumab or 240 mg of nivolumab in addition to 2 x 10

 cells. No grade 2 or 3 toxicities were reported in any patients that received ICI and SNK01 combination doses.

The best response was seen in the patient with SRCS who, as of August 2022, has remained in remission through 24 months and 36 combination doses of pembrolizumab and SNK01 and has no evidence of disease and no toxicities. This patient had a PDL1-negative tumor and whose disease was refractory to 5 prior lines of therapy. The patient with uterine sarcoma (PD-L1 negative) had a partial response and the patient with chondrosarcoma (10% PD-L1) had a partial response but died from complications from surgery.

The patients with leiomyosarcoma, osteosarcoma, and sarcoma NOS passed away prior to receiving the combination dose while the patients with pleomorphic sarcoma (20% PD-L1) and mucinous adenocarcinoma (25% PD-L1) experienced disease progression. Patients whose disease progressed reported quality of life improvements and became eligible for salvage chemotherapy, resulting in additional clinical response.

“SNK01 combined with CIs appears to be safe and demonstrates clinical activity against several types of heavily pre-treated advanced sarcoma, independent of PD-L1 status. It may also keep rapidly progressing disease stable enough to allow additional cytotoxic chemotherapy. This intriguing combo data warrants further study,” Chua and colleagues wrote.

Chua VS, Chawla SP, Gordon EM, et al. USFDA authorized compassionate use of SNK01 (autologous non-genetically modified natural killer cells with enhanced cytotoxicity) and checkpoint inhibitors in advanced heavily pre-treated sarcoma: A promising regimen. Presented at: ESMO Congress 2022, September 9-13, Paris, France. Poster #757P

The FDA authorized the natural killer cell therapy combo for compassionate use.

Plans for a phase 1 clinical trial (NCT05274451) for LYL797, an autologous investigational ROR1-targeted chimeric antigen receptor (CAR) T-cell therapy, which has begun screening patients, were detailed in a poster exhibited at the 

LYL797 incorporates Gen-R technology, which is a form of genetic reprogramming intended to overcome T-cell exhaustion, and Epi-R technology, a form of epigenetic reprogramming which is intended to generate T-cells with properties of durable stemness via an optimized manufacturing process. It is under investigation for the treatment of relapsed/refractory (r/r) triple-negative 

 (TNBC) and non-small cell lung cancer (NSCLC). Improved functional activity compared to ROR-1-targeted CAR-T therapies without the 2 forms of reprogramming was demonstrated in preclinical studies in models of ROR1+ TNBC and NSCLC tumors. LYL797 is being developed by Lyell Immunopharma, which announced the FDA’s clearance of its investigational new drug (IND) application for the therapy late last year.

“While CAR T-cell therapies have proven effective in hematologic malignancies, patients with solid tumors have seen limited benefit from these approaches due to a tumor microenvironment that leads to T-cell exhaustion and a loss of durable stemness,” Tina Albertson, MD, PhD, chief medical officer and head of development, Lyell Immunopharma, said in a December 2021 statement regarding the IND clearance.

 “LYL797 is the first program to clinically evaluate our 2 T-cell reprogramming technologies which are designed to overcome these barriers, with the goal of developing more effective therapies for patients with solid tumor cancers.”

The multi-center, single-arm, open-label, dose-escalation and dose-expansion trial will recruit up to 54 patients aged 18 years or older with locally advanced or metastatic, unresectable ROR1+ TNBC or NSCLC.

 Participants are required to have measurable disease which includes a target lesion plus 1 additional lesion for biopsy, unless the target lesion is greater than or equal to 30 mm. Patients must additionally be r/r after having received 2 or more previous lines of therapy, have adequate organ and marrow function, and have an Eastern Cooperative Oncology Group Performance Status score of 0 to 1 with a life expectancy greater than 3 months. Patients with active central nervous system disease or leptomeningeal disease, and patients who have undergone prior treatment with solid organ transplant, adoptive T-cell therapy, or anti-ROR1 therapy will be excluded from the study. However, patients with previously treated brain metastases, if stable, may be included. Additional exclusion criteria relate to patient health status, caregiver access, and locality to the treating facility.

The dose-escalation phase will enroll TNBC patients at 4 planned dose levels, with a 28-day dose-limiting toxicity (DLT) monitoring period, and will continue dose escalation until a recommended phase 2 dose (RP2D) is determined. The dose expansion phase will enroll 15 patients with TNBC and 15 patients with 

 at the RP2D. Patients will be pretreated with fludarabine and cyclophosphamide after leukapheresis and manufacturing, before receiving a single-dose infusion of LYL7978. Primary end points include the incidence of DLTs and the incidence and severity of treatment-emergent adverse events. Secondary end points include overall response rate, complete response rate, duration of response, progression-free survival, overall survival, and pharmacokinetic parameters. Exploratory end points include memory, activation, and exhaustion status of LYL797 CAR-T cells in the blood infusion product; ex vivo functional activity of LYL797 CAR-T cells before and after infusion; correlation between tumor-specific ROR1 expression and clinical activity; tumor infiltration; and tumor-specific expression of ROR1 and immune activation/resistance markers before and after treatment. The trial is recruiting at multiple locations in the United States and is estimated to be completed in September 2026.

1. Spigel DR, Murthy HS, Chumsri S, et al.Phase I study of LYL797, a ROR1-targeted CAR T-cell therapy with genetic and epigenetic reprogramming for the treatment of advanced solid tumors. Presented at: 2022 ESMO Congress. September 9-13, 2022; Paris, France. Abstract 777TiP

2. Lyell Immunopharma announces FDA clearance of its IND for LYL797, a CAR T-cell therapy incorporating novel reprogramming technologies for solid tumors. News release. Lyell Immunopharma, Inc. December 16, 2021. 

https://ir.lyell.com/news-releases/news-release-details/lyell-immunopharma-announces-fda-clearance-its-ind-lyl797-car-t

Improved functional activity compared to ROR-1-targeted CAR-T therapies without the 2 forms of reprogramming was demonstrated in preclinical studies. 

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