Where Are the Next-Generation Cell Therapy Opportunities? Insights from the 2023 AACR Annual Meeting

From April 14 to 19, the annual AACR Annual Meeting resumed in-person proceedings. This highly anticipated event in the field of oncology drew approximately 20,000 attendees this year, essentially restoring its pre-pandemic scale.

Numerous Chinese pharmaceutical companies actively participated in the conference, with their numbers steadily increasing in recent years. Not only did biotech firms present their latest research findings, but many companies providing CRO services and upstream life science tools also attended to expand their overseas client base and seek collaborations. An industry insider at the event told VCBeat New Medicine, “The atmosphere on-site was quite exciting and positive, with booths from dozens of Chinese companies visible.”

VCBeat’s New Medicine has observed that following the surge of interest in antibody-drug conjugates (ADCs) at last year’s ASCO Annual Meeting, this momentum has carried over to this year’s AACR Annual Meeting. However, attention toward the cell therapy sector has waned, with sentiment becoming more measured.

Some investors focused on the cell therapy sector are no longer fixated solely on the AACR Annual Meeting. In their view, current technological innovations in cell therapy resemble incremental optimizations and improvements within specific niches, with many companies differentiating themselves through distinct technical pathways. These innovations are unlikely to be as groundbreaking as Kymriah, the first CAR-T product approved in 2017, nor will they generate significant market buzz.

Dr. Luo Wangqian, a partner at Huafang Capital, began focusing on the cell therapy sector as early as 2017, witnessing the industry’s entire trajectory from decline to prosperity. However, in the past two years,He has observed that the growing expectations for breakthroughs in cell therapy for solid tumors are beginning to return to a more rational level.“After Novartis’ CAR-T product was launched in 2017, any conference even remotely related to CAR-T was so overcrowded that people were standing in the aisles. However, the industry is now experiencing a bottleneck period. At this conference, attendees may at most observe which companies have made incremental advances in specific areas.”

However, Luo Wangqian also believes that technological innovation is necessary, and tumor immunotherapy has now entered a phase of quantitative accumulation.“Actually, every niche segment within cell therapy presents opportunities, such as in the treatment of solid tumors,”I believe that we cannot rely solely on a single technology. Much like modern warfare, where victory is not achieved by one or two new weapons alone, what is needed is systemic countermeasure capability. This requires a well-coordinated combination of multiple approaches, strategically deployed based on a deep understanding of the immune system. At this year’s AACR meeting, I saw research being conducted on hybrid TCR and CAR designs, which I consider a very promising direction.”

Indeed, at this year’s AACR Annual Meeting, more novel cell therapy technologies began transitioning from conceptual stages to validation. Many biotech companies specializing in next-generation cell therapies are focusing on increasingly niche areas, aiming to achieve differentiation through technological innovation.

“Currently, these technological innovations are focused on three key issues: first, how to reduce costs and make cell therapy accessible to more patients; second, how to address the efficacy of cell therapy in solid tumors; and third, how to enhance safety by mitigating the potential toxicity associated with targeting TAA antigens.“Dr. Hao Ruidong, Senior Director of R&D at Yimufeng, explained to VCBeat.”

Addressing these three issues has become the central theme of the cell therapy track at this year’s AACR Annual Meeting.

We observe that various therapeutic modalities, including CAR-T and CAR-NK therapies, as well as early-stage iNKT cell and T-cell engager therapies, are actively pursuing strategies to overcome these bottlenecks.

Universal CAR-T, which has always attracted significant attention, saw its most representative company, Allogene, present data on its candidate product ALLO-316 for the treatment of renal cell carcinoma at the conference.“Allogene’s latest data holds significance in two aspects. First, the study focused on renal cell carcinoma, a type of solid tumor, and achieved an objective response rate (ORR) of 30%, which is a respectable outcome, demonstrating that the company’s UCAR-T technology is robust. Second, the target of this project is CD70, and the data further validates the feasibility of this target. Therefore, I believe that universal CAR-T therapies have yielded some notable results at this conference,” analyzed Hao Ruidong.

Similarly,CAR-NK Therapy Remains a Key Industry Focus. In addition to established player Century Therapeutics reaffirming proof-of-concept for its iPSC-derived cell therapy platform with updated results, Senti Bio has demonstrated technological foresight by integrating logic-gated technology with CAR-NK therapy.

Hao Ruidong was deeply impressed by the results recently released by Senti Bio. “Senti Bio has announced a significant number of findings this year. First, in the area of logic-gated CAR-NK cells, the company developed a NOT logic gate that not only activates against tumor targets but also incorporates a target expressed by normal tissues. Upon contact with these normal tissue targets, CAR activity is inhibited, thereby enabling CAR-NK cells to selectively kill tumor cells while sparing normal tissues. Their preclinical data appear quite promising. Additionally, to address tumor heterogeneity, Senti Bio has engineered dual-targeting combined with logic gating. In another study, they utilized tumor-specific proteases to promote the release of IL-15, thereby enhancing the anti-tumor activity of CAR-NK cells. These studies are all quite intriguing.”

Many conceptual technologies, such as armored CAR-T, logic-gated CAR-T, and γδ T cell CAR-T, were also showcased at this year’s AACR Annual Meeting.Among these, armored CAR-T primarily addresses the challenge of treating refractory solid tumors. Scientists have attempted to "arm" CARs to enhance the survival and proliferation of T cells within the harsh tumor microenvironment, thereby boosting their cytotoxic efficacy. Logic-gated CAR-T focuses more on reducing the toxicity of CAR-T therapy by controlling the activation of CAR-T cells, thus lowering the likelihood of "on-target/off-tumor" toxicity. γδT cell-based CAR-T therapy also addresses off-target effects and toxicity issues. This technology aims to leverage the innate immune recognition capabilities of γδT cells to distinguish between tumor and healthy tissues, offering a targeted approach with potentially lower toxicity.

In response to these technological innovations, companies such as Cellectis, Arsenal Bio, and IN8bio presented their related findings at the conference.

Furthermore, more cell therapy technologies in the early stages of research and development also took the stage at AACR.iNKT therapy company MiNK Therapeutics and T-cell engager company Harpoon Therapeutics will both announce a series of results on their respective product pipelines., they both represent the development direction of the new generation of cell therapies.

Based on the numerous findings presented in the cell therapy track at this year’s AACR Annual Meeting, VCBeat has selected eight representative companies to provide a comprehensive overview of advances in cell therapy.

Focus Areas:Universal CAR-T

AACR Announces Research:Preclinical Results of MUC1 CAR-T

Founded in 1999, Cellectis has nearly 24 years of development history. This star enterprise has been dedicated to the development of universal CAR-T therapies using its gene-editing technology, TALEN, and its electroporation system, pulseAgile, making it one of the earliest companies to establish a presence in the UCAR-T cell therapy field. Currently, Cellectis has six pipelines in Phase I clinical trials, covering indications for both hematologic malignancies and solid tumors.

At the AACR Annual Meeting, Cellectis presented preclinical results for its new candidate product, MUC1 CAR-T, a universal armored CAR-T therapy whose most notable feature is the integration of universal CAR-T and armored CAR-T technologies.

MUC1 CAR-T targets MUC1, and Cellectis hopes that this product will first achieve a breakthrough in the treatment of relapsed or refractory triple-negative breast cancer (TNBC).

According to the company, this MUC1 CAR-T cell therapy incorporates up to four TALEN-mediated knockouts and two TALEN-mediated insertions. Preclinical data indicate that MUC1 CAR-T cells demonstrate superior therapeutic efficacy and safety within immunosuppressive tumor microenvironments. Intratumoral delivery of antigen-specific CAR-T cells effectively controlled tumor growth, with MUC1 CAR-T cells exhibiting superior activity in both tumor clearance and normal glandular restoration.

Focus Areas:Universal CAR-T

AACR Announces Research:Phase I Clinical Data of ALLO-316

Allogene is one of the pioneers in universal CAR-T therapy. The company was co-founded in 2018 by Arie Belldegrun, founder and CEO of Kite Pharma, and Dr. David Chang, former Executive Vice President of Research and Development and Chief Medical Officer at Kite. Since its inception, Allogene has established collaborations with multiple renowned biopharmaceutical companies, including Pfizer, Cellectis, and Servier. Its high-profile background has consistently drawn significant industry attention to its research achievements.

At this year’s AACR Annual Meeting, Allogene presented Phase I clinical data for its off-the-shelf CAR-T candidate ALLO-316 in the treatment of renal cell carcinoma. According to Allogene, ALLO-316 targets CD70 and utilizes the company’s proprietary Dagger^TMTechnological enhancements aim to mitigate the rejection resistance of universal CAR-T cells, improve patient cell expansion, and enhance persistence.

According to the Phase I clinical data released, as of March 23, 2023, a total of 19 patients participated in the Phase I clinical trial, among whom 10 patients with renal cell carcinoma expressed CD70. The results indicate that ALLO-316 demonstrates early anti-tumor activity, with responses deepening over time. Anti-tumor activity was primarily observed in patients expressing CD70. Among the 18 patients evaluable for efficacy, the disease control rate (DCR) was 89%. In the 10 patients with known CD70-positive tumors, the DCR reached 100%, including three patients who achieved partial response. The longest duration of response to ALLO-316 extended to eight months, and patients with higher levels of CD70 expression showed a trend toward tumor shrinkage.

Focus Areas:T-Cell Therapy for Solid Tumors

AACR Announces Research:Logic-Gated CAR-T, AB-2100

Arsenal Bio, founded in 2019, is a biotechnology company focused on T-cell therapies for solid tumors. It is dedicated to programming T cells using synthetic biology technologies to develop next-generation therapeutics. Arsenal Bio has also attracted significant attention; in 2022, the company completed a $220 million Series B financing round, marking the second-largest single transaction in the cell therapy field last year. Furthermore, Arsenal Bio has garnered favor from multinational corporations (MNCs) such as Bristol Myers Squibb (BMS) and Roche. BMS not only provided financial support during Arsenal Bio’s Series B round but also established a long-term collaboration with the company. Meanwhile, Genentech, a member of the Roche Group, entered into a long-term partnership agreement with Arsenal Bio following its Series B financing, jointly deploying Arsenal Bio’s proprietary technologies for T-cell engineering and high-throughput screening.

At this year’s AACR Annual Meeting, Arsenal Bio presented six abstracts focused on the application of logic-gated CAR-T cell technology. The results demonstrated that the company’s proprietary integrated circuit T-cell approach holds promise for the treatment of ovarian cancer, renal cancer, and other solid tumors, with continued progress being made.

Meanwhile, Arsenal Bio also disclosed its candidate product AB-2100.AB-2100 is a novel integrated circuit T-cell therapy candidate designed to treat clear cell renal cell carcinoma. As the company’s second pipeline asset, it aims to initiate Phase I clinical trials in 2024.

Focus Areas:γδT Cell Therapy

AACR Announces Research:Preclinical Data for the nsCAR Platform and INB-330

IN8bio focuses on the discovery, development, and commercialization of CAR-T candidate products targeting γ-δ T cells for the treatment of solid tumors and hematologic malignancies. The company primarily leverages the innate immune recognition capabilities of γ-δ T cells to distinguish between tumor and healthy tissues, thereby offering targeted CAR-T therapies with potentially lower toxicity.

IN8bio is currently developing CAR-T candidates based on its γδ T cell platform and conducting two Phase I clinical trials: INB-200 for the treatment of newly diagnosed glioblastoma, and INB-100 for the treatment of leukemia patients undergoing hematopoietic stem cell transplantation.

At this AACR Annual Meeting, IN8bio not only presented preclinical data on its novel non-signaling CAR (nsCAR) platform but also announced a new program—INB-330, targeting CD33 in acute myeloid leukemia.

nsCAR is a technology platform developed by IN8bio that leverages the innate ability of γ-δ T cells to distinguish between healthy and malignant tissues. The company first conducted a proof-of-concept study to evaluate the selective tumor-targeting capability of nsCAR technology using CD19 as the target. The preliminary data released demonstrate that, under conditions where both cell types express the CD19 antigen, γ-δ CD19 nsCAR T cells eliminated 80% of leukemia cells while killing only 5% of healthy B cells, highlighting its superior efficacy.

In the newly launched INB-300 project, Ns33CAR cells were able to distinguish between leukemic cells uniformly expressing CD33 and healthy monocytes isolated from peripheral blood. Preliminary results confirmed that Ns33CAR exhibits anti-cancer activity against cell lines of acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), and chronic myeloid leukemia (CML).

Focus Areas:iPSC-derived CAR-NK, allogeneic CAR-T

AACR Announces Research:Preclinical Data of the iPSC-Based Cell Therapy Platform

Century Therapeutics, founded in 2018, specializes in allogeneic, induced pluripotent stem cell (iPSC)-derived CAR-NK and CAR-T cell therapies. Currently, Century is building an allogeneic iPSC-derived cell therapy platform that integrates gene editing, protein engineering, technology development, and manufacturing capabilities to generate allogeneic, iPSC-derived NK and T cells for the treatment of hematologic malignancies and solid tumors.

At this year’s AACR Annual Meeting, Century Therapeutics presented preclinical data from its iPSC-based cell therapy platform, validated through its candidate product CNTY-101.

CNTY-101 is indicated for the treatment of B-cell malignancies and incorporates a total of six gene edits. Century evaluated 28 clinical clone candidates of CNTY-101, revealing that the number of donor and integrated transgene alleles significantly impacts clone functionality.

Focus Areas:CAR-NK Therapy

AACR Presents Research:Preclinical Data of SENTI-202, SENTI-301A, and crIL-15 CAR-NK Products

Senti Bio is a startup that designs gene and cell therapies using genetically engineered circuit technology, co-founded by synthetic biology pioneer James J. Collins and his student Guan-Da Lu, among others. Currently, Senti Bio’s oncology pipeline focuses on three preclinical projects, all of which are CAR-NK cell therapies: SENTI-202, which targets and eliminates acute myeloid leukemia (AML) cells; SENTI-301, for the treatment of hepatocellular carcinoma; and SENTI-401, which targets and eliminates colorectal cancer (CRC) cells.

At the 2023 AACR Annual Meeting, Senti Bio presented three abstracts, primarily featuring preclinical data on SENTI-202, SENTI-301A, and crIL-15 CAR-NK products. The data showed:

• Compared with non-engineered NK cells in in vitro and in vivo AML models, SENTI-202 demonstrated enhanced cytotoxicity and activity, capable of killing primary tumor-derived cells from patients with AML and MDS;

• SENTI-301A demonstrated CAR-driven, antigen-specific activity against target cell lines and exhibited enhanced cytotoxic activity in vitro against both HCC and non-HCC GPC3-expressing cell lines;

• In the crIL-15 CAR-NK project, incorporating crIL-15 into the gene circuit enhances the persistence and cytotoxic activity of CAR-NK cells and activates adjacent T cells and NK cells. In AML xenograft models, CAR-NK cells engineered with crIL-15 technology significantly reduced tumor burden and prolonged mouse survival compared to unengineered NK cells.

Focus Areas:iNKT Cell Therapy

AACR Announces Research:Phase I/II Clinical Data of T-797

MiNK Therapeutics, founded in 2017, is a clinical-stage biopharmaceutical company dedicated to developing potentially first-in-class novel engineered iNKT cell therapies and bispecific iNKT cell engager platforms for the treatment of cancers and other immune-mediated diseases with high unmet medical needs. Since its inception, the company has established a pipeline of natural and engineered iNKT cell therapies intended for development in solid tumors, relapsed or refractory multiple myeloma, graft-versus-host disease (GvHD), and acute respiratory distress syndrome (ARDS) secondary to COVID-19.

At the AACR Annual Meeting, MiNK Therapeutics presented Phase I/II clinical data on T-797, an allogeneic iNKT cell therapy, in solid tumors. The data demonstrated that T-797 can induce systemic and local anti-tumor responses, promote immune cell infiltration into tumors, and enhance immune cell activation. T-797 showed activity in patients with refractory solid tumors, either as monotherapy or in combination with anti-PD-1 therapy. In patients with metastatic gastric cancer who had progressed on pembrolizumab and nivolumab/FOLFOX, T-797 induced partial responses, resulting in a 42% reduction in tumor size that lasted for more than nine months. Furthermore, T-797 persisted and remained detectable in peripheral blood for over eight weeks. No neurotoxicity, dose-limiting toxicities, or severe cytokine release syndrome (grade >3) were observed.

Focus Areas:T-cell engager

AACR Announces Study:Preclinical Results of ITGB6 ProTriTAC, TROP2 ProTriTAC, HPN217, and HPN328

Harpoon Therapeutics is a clinical-stage immuno-oncology company primarily focused on T-cell engager therapies, which harness the natural power of T cells to combat cancer and other diseases. T-cell engagers are bioengineered proteins that direct patients’ own T cells to kill target cells. One end binds to surface antigens on cancer cells, while the other end binds to surface receptors on T cells, thereby stimulating the T cells to destroy the cancer cells.

At the core and foundation of Harpoon is its TriTAC (Trispecific T-cell Activating Construct) antibody-derived platform. The company has primarily leveraged the TriTAC platform to develop a series of therapeutic approaches for solid tumors and hematologic malignancies. Currently, Harpoon has three candidate products that have entered clinical trials. In terms of technological platforms, in addition to TriTAC, Harpoon has also established two other antibody platforms: ProTriTAC and TriTAC-XR.

At this year’s AACR Annual Meeting, Harpoon Therapeutics presented six abstracts, showcasing preclinical data for two drug candidates targeting TROP2 and ITGB6 in solid tumors—namely, ITGB6 ProTriTAC and TROP2 ProTriTAC—as well as preclinical results for its novel T-cell engager therapies, HPN217 and HPN328.

• ITGB6 ProTriTAC is a protease-activated, ITGB6-targeting T-cell engager prodrug, designed using Harpoon’s ProTriTAC™ platform. Data show that in rodent tumor models, ITGB6 ProTriTAC demonstrates effective in vivo prodrug activation and potent antitumor activity, achieving complete tumor eradication at doses as low as 30 μg/kg. In cynomolgus monkeys, ITGB6 ProTriTAC exhibits favorable pharmacokinetics and safety profiles, with good tolerability up to the highest tested dose of 540 μg/kg.

• TROP2 ProTriTAC is a protease-activated, TROP2-targeted T-cell engager prodrug, with its drug design also derived from Harpoon’s ProTriTAC™ platform. In rodent tumor models, TROP2 ProTriTAC demonstrated potent antitumor activity in vivo, achieving complete tumor eradication at doses as low as 30 μg/kg. In cynomolgus monkeys, TROP2 ProTriTAC exhibited favorable pharmacokinetics and was well tolerated at doses up to 180 μg/kg.

• HPN328 targets DLL3. In preclinical immunocompetent mouse models, HPN328 demonstrated dose-dependent antitumor activity and enhanced activation of CD8+ tumor-infiltrating lymphocytes (TILs). These results suggest that HPN328 can induce epitope spreading and prolong antitumor immunity by increasing memory T cells, potentially leading to more durable antitumor responses in cancer patients.

• HPN217 targets BCMA. In preclinical mouse models, γ-secretase inhibitors enhanced the potency of HPN217 across various in vitro cell lines. Compared with monotherapy, combination therapy with 1 mg/kg LY-3039478 and 4 μg/kg HPN217 reduced the tumor burden targeted by T cells and improved survival rates.