A recent report on the long-term responses in the first leukemia patients dosed over ten years ago with CAR-T cells revealed sustained remission and the presence of persistent CD4+ CAR-T cell populations (Melenhorst et al. 2022). The success of CAR-T cells in various hematological malignancies has spurred much research into developing similarly effective immunotherapies against solid tumors. Nevertheless, the success of immunotherapies against solid tumors has been limited by multiple factors, such as immunosuppression within the tumor microenvironment (e.g., regulatory T cells, tumor-associated macrophages), limited tumor-specific antigens to stave-off on-target-off-tumor toxicities, and obstacles to tumor drug delivery (e.g., intra-tumoral pressure) (Guha et al. 2022).
At AACR2023, the “Promising Novel Antitumor Strategies in Early Phase Clinical Trials” session highlighted progress in evaluating new immunotherapy strategies targeting solid tumor antigens.
Dr. Samer Srour from the University of Texas MD Anderson Cancer Center presented an update on phase 1 multicenter study (TRAVERSE), which aims to evaluate the safety and efficacy of ALLO-316 in patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC). ALLO-316 is an allogeneic CAR-T cell targeting CD70.
Phase 1 multicenter study (TRAVERSE). Samer Srour is an Assistant Professor of Medicine in the Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center. AACR2023: Promising Novel Antitumor Strategies in Early Phase Clinical Trials
Why CD70? As is typical for other identified tumor-associated antigens (TAAs), CD70 represents an attractive therapeutic target for its restricted and low expression in normal tissues (i.e., immune cells such as T, B, and NK cells), yet CD70 is highly prevalent in several solid tumor tissues. For example, CD70 is overexpressed in RCC tissues and quickly internalized upon antibody binding, making it a relevant target for antibody-cytotoxic drug conjugate (ADC) therapy (Adam et al. 2006). Additionally, the interaction between CD70 and its CD27 receptor is linked to immunosuppression and immune evasion in solid tumors (Flieswasser et al. 2022). Therefore, antibody-based or cell-based strategies targeting CD70 could help inhibit the tumor-promoting effects of this pathway.
Unfortunately, the progress of anti-CD70 ADCs indicated for RCC has stalled, with studies on four candidates not progressing beyond the first phase of clinical trials. In contrast, clinical studies on CAR-T cell therapies targeting CD70 in RCC, while still at early stages, continue to progress (e.g., CTX130 (CAR) CRISPR Therapeutics, ALLO 316 (CAR) Allogene Therapeutics) (Flieswasser et al. 2022).
Relapsed and refractive clear cell renal cell carcinoma patients for whom approved treatments have failed, such as checkpoint and Tyrosine kinase inhibitors, are missing effective curative options. Allogeneic cell therapies present various benefits for cancer patients unresponsive to previous treatments. First, donor-derived cells are an off-the-shelf therapy, reducing the time to treatment. Second, an allogeneic approach allows the development of cellular therapies for those patients unable to use their T cells. For instance, patients previously exposed to chemotherapies may have a limited supply or defective T cells that prevent the manufacturing of autologous CAR-T cells (Sanber et al. 2021). Last, ready-made T cells reduce the overall cost of highly personalized therapies.
Despite these benefits, allogeneic cell therapies carry various risks, such as potentially inducing adverse immune reactions due to transplanted cells attacking the recipient’s tissues (i.e., graft-versus-host risk, GvHD). Therefore, ALLO-316 was developed with several safety features, including the knockout of the T cell receptor (TCR) and CD52. These modifications help prevent GvHD and make possible the use of monoclonal antibodies to CD52 to deplete lymphocytes before infusion, extending CAR-T cells' persistence. Additionally, the ALLO-316 CAR construct contains a CD20 domain that may be targeted with Rituximab to eliminate the infused CAR-T cells if toxicity occurs. Lastly, Allogene Therapeutics’ proprietary technology, “Dagger,” has been implemented in the ALLO-316 product to help prevent CAR-T cell rejection and improve expansion and persistence. Based on an Allogene Therapeutics’ recent press release, “The Dagger platform arms AlloCAR T cells with a CD70-targeting receptor designed to recognize and deplete CD70 positive host cells while also masking the CD70 molecule expressed on the AlloCAR T cells themselves, preventing fratricide” (Cassiano C. 2023).
ALLO-316 is an allogeneic CAR-T cell product. ALLO-316 cells express a CAR construct consisting of a human anti-CD70 scFv, a rituximab-binding domain off-switch, and 4-1BB and CD3ζ signaling domains. Additionally, these cells lack the expression of the TCR and CD52 genes. Retrieved from “https://allogene.com/wp-content/uploads/2021/09/A_Fratricide_Resistant_Allogeneic_CAR_T_Targeting_CD70.pdf” without modifications.
As shared by Dr. Srour at AACR2023, the TRAVERSE study evaluates several ALLO-316 doses and conditioning treatments to elucidate safety, tolerability, and tumor-killing activity. Although the study group remains small, with only 19 infused patients, ALLO-316 shows a safety profile similar to autologous CAR-T cell therapies. Notably, most patients responded to treatment, resulting in a high disease control rate (DCR) of 89%, which increased to 100% for patients with confirmed CD70-expressing tumors.
Despite the small number of patients, tumor reduction was observed to correlate with CD70 expression level. After a single infusion, responses persisted beyond four months for more than half of the patients with CD70-positive tumors. Among those, two patients infused with a second dose after ~8 months continued to respond favorably to the treatment. Promisingly, high CAR-T cell expansion occurred in most patients, and evidence of long persistence and good tumor infiltration was also observed in some patients. Dr. Srour stressed how the novel Dagger effect mechanism is helping ALLO-316 to persist longer by eliminating CD70-positive host T cells. With these encouraging early results, recruitment for the TRAVERSE study continues as it moves to expand doses and indications during this year.
Dr. Ezra Cohen from the University of California San Diego Health reported early clinical findings with Petosemtamab in advanced head and neck squamous cell carcinoma (HNSCC). Petosemtamab is a fully humanized bispecific antibody targeting the epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5). Among these two targets, EGFR is well characterized and frequently mutated in different solid cancers. In contrast, LGR5 is a less well-known target predominantly expressed in cancer stem cells and overexpressed in various solid tumors (e.g., colorectal cancer (CRC), hepatocellular carcinoma (HCC), and HNSCC).
LGR5, also known as G protein-coupled receptor 49 (GPR49), was first characterized in 1998 and plays a role in activating Wnt/β-catenin signaling, thereby promoting cancer stem cell proliferation (Xu et al. 2019). Preclinical studies in models of gastrointestinal cancers showed that targeting LGR5 with ADCs could effectively decrease tumor size and proliferation. Furthermore, despite LGR5 being expressed in normal intestinal stem cells, these studies found that a safe therapeutic window could be achieved by optimally engineering anti-LGR5 ADCs (Junttila et al. 2015).
Currently, very few therapeutic candidates targeting LGR5 have reached clinical studies. Besides Petosemtamab, only one other study leverages this target in cancer therapy. CNA3103, an anti-LGR5 autologous CAR-T Cell therapy, is being evaluated for clinical use in patients with metastatic CRC (NCT05759728).
Clinical activity of MCLA-158 (petosemtamab). Ezra Cohen, MD, is Chief of the Division of Hematology-Oncology, Co-Director of the San Diego Center for Precision Immunotherapy, Co-Director of the Center for Precision Immunotherapy, and Co-Director of the IEM Center for Engineering in Cancer at UC San Diego Health. AACR2023: Promising Novel Antitumor Strategies in Early Phase Clinical Trials
Preclinical findings previously demonstrated MCLA-158 or Petosemtamab to be effective at inhibiting tumor growth and blocking metastasis (Herpers et al. 2022). Petosemtamab is known to work via several mechanisms, including blockade of EGFR signaling, EGFR degradation in LGR5 expressing cancer stem cells, and lastly by promoting immune cell interactions with cancer cells resulting in antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP).
MCLA-158 (Petosemtamab) bispecific antibody. Petosemtamab targets and eliminates cancer stem cells involved in tumor growth and metastasis. Retrieved without modification from “https://seekingalpha.com/article/4273484-kicking-tires-on-merus.”
HNSCC has a high prevalence and mortality and is among the top ten most common cancer types globally (Johnson et al. 2020). Unfortunately, no therapeutic options are available for patients not responding to approved treatments, such as platinum-based chemotherapy and checkpoint inhibition (i.e., anti-PD-1). Therefore, the current early-phase clinical study sponsored by Merus N.V. looks at targeting EGFR and LGR5, both TAAs frequently overexpressed in HNSCC (Rehmani and Issaeva 2020).
At AACR2023, Dr. Cohen provided an update on the responses to Petosemtamab infused every two weeks in patients with incurable HNSCC. Among a group of 43 patients treated, 72% responded to Petosemtamab, achieving stable disease, partial, and even complete responses. Significantly, 28% of these patients remain on treatment as they continue to respond favorably to Petosemtamab, with several responding past the first year. Therefore, Petosemtamab may provide a new effective alternative for patients with refractive and heavily pre-treated HNSCC. Overall, these early findings are prompting further evaluation of Petosemtamab as monotherapy and in combination with checkpoint inhibitors for recurrent and metastatic HNSCC.
