CAR T cell therapy has revolutionized the treatment of many blood cancers, but has shown little success against solid tumors, which account for more than 85% of all cancers.
Columbia University researchers have now developed a new form of highly sensitive CAR T cells, known as HIT T cells, that aims to overcome one of the biggest barriers in solid tumor immunotherapies, which is the way that solid tumors lack a single, widely shared surface target.
Headed by Michel Sadelain, MD, PhD, director Columbia Initiative in Cell Engineering and Therapy (CICET), the researchers engineered an ultra-sensitive and highly selective chimeric antigen receptor called an HLA-independent T cell (HIT) receptor, which is capable of detecting even the smallest amounts of the protein CD70 on tumor cells.
Eradicating tumors in preclinical models
The team reported that these CD70-HIT cells were able to eradicate kidney, ovarian, and pancreatic tumors in preclinical models. “Curing solid tumors is not easy, but this work solves one piece of the puzzle,” said Sadelain, who pioneered today’s CAR T therapies, which reprogram a patient’s own immune cells to become trained assassins that seek and destroy the patient’s cancer. For the past few years, his lab has also led the development of HIT cell therapy.
Sophie Hanina, PhD, a research associate scientist at CICET, commented, “HIT cells are the next generation of CAR T cells. They can be programmed like a CAR T cell, but they have the sensitivity of a natural T cell and can detect cancer cells that have only a vanishingly small number of target molecules.” Speaking to GEN, Hanina added, “CD70 serves as a prototype target to uncover other immunotherapeutic targets which may appear negative by standard methods but are still positive (has (“stealth”) expression on tumor cells …). Using a more sensitive receptor like HIT, these stealth targets can be effectively recognized, expanding the range of tumors that next-generation HIT receptors can eliminate.”
Senior author Sadelain, together with first author Hanina, and colleagues, reported on their development in Science, in a paper titled “Sensitive CAR T cells redefine targetable CD70 expression in solid tumors,” concluding, “These findings provide a potential strategy to treat a broad range of solid tumors.”
Chimeric antigen receptors (CARs) are engineered molecular “homing devices” that augment the functions of immune cells to recognize and attack specific disease targets. CAR T cells targeting CD19 have transformed the treatment of certain blood cancers and have shown success in producing lasting remissions in patients who have shown resistance to other therapies.
Cell therapy challenges
Though several obstacles are known to thwart CAR T cell activity in solid cancers, the first challenge for any cell therapy is to locate every cancer cell. Blood cancer cells are usually easy for CAR T to spot, as each is covered with numerous CD19 molecules that act as a homing beacon for the CAR T cells.
However, unlike many blood cancers, solid tumors lack a single, widely shared surface target that is consistently present on cancer cells and largely absent from healthy tissues. “Unlike CD19 for B cell malignancies, no target with pan-cellular expression in solid tumors and absence in normal vital cells has been identified,” the authors wrote. “Efficacious targeting of solid tumors is thus compromised by heterogeneous target expression, which limits CAR T cell efficacy, and target expression in normal tissues, which precludes the use of potent T cells to avert unacceptable toxicities. There is at present a dearth of common, effective CAR targets in solid tumors.”
Previous studies have suggested that CD70 could be a promising target for future CAR T immunotherapies, as it is abnormally overproduced in several solid tumors. “Its prevalence in 70 to 80% of clear cell renal cell carcinoma (ccRCC) and ovarian cancer, and 25% of pancreatic cancer, makes CD70 a highly valuable target across a range of cancers,” the researchers stated.
Heterogeneous target expression
Yet CD70 expression within these tumors is uneven—some cancer cells display it abundantly while others express little or none. “… CD70 expression in tumors is typically heterogeneous, with some tumor findings position CD70 as an excellent immunotherapeutic target, but only if a highly sensitive targeting receptor is used,” they further commented.
“Some molecules have been identified that are found in 25%, 50%, or 75% of tumor cells, says Sadelain, who is also the Herbert and Florence Irving Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons. “Though a therapy directed at those targets might be successful in eliminating some tumor cells, you can’t cure somebody if you just eliminate a small fraction or even 90% of their tumor. You have to get down to the very last cell.”
While previous studies had suggested CD70 levels vary from cell to cell in a tumor, Hanina had a hunch those studies were missing cells that contained CD70 molecules, but at very low levels. To better understand the limitations of CAR therapy in these tumors, Hanina and colleagues developed patient-derived xenograft laboratory models that recreate the patchwork expression of CD70 seen in patients with kidney cancer. “It was critical to develop patient-derived xenograft models, which had been derived from multiply treated and refractory patients,” Hanina commented to GEN. “These models accurately recapitulated both the antigen heterogeneity seen in patient tumors and also the CAR T cell failures observed in clinical trials to date.”
A spectrum of CD70 expression
Hanina and team created new methods to detect the molecule, finding that CD70 levels vary widely on cancer cells, but that all cells have at least a few on their surfaces. The researchers found that CD70 expression exists on a spectrum in all tumor cells, and even those labeled CD70-negative expressed very low levels of CD70, though not at a level high enough to be detected and destroyed by conventional CAR T cells. “… we found that apparent CD70-negative tumor cells do in fact express low levels of CD70, though not at a level high enough to be eliminated by conventional CAR T cells.”
Conventional CAR T cells can only detect cancer cells that possess a high level of the target molecule. Hanina saw that when she tested CD70 CAR T cells against solid tumors in the laboratory, explaining why CAR T therapies programmed to target CD70 have not performed well in patients with solid cancers.
Eliminating tumor cells with lower antigen levels
The authors then engineered a far more sensitive and highly selective chimeric antigen receptor, called HLA-independent T cell (HIT) receptor, a technology under development in Sadelain’s lab at CICET. “The HIT technology was developed in the Sadelain lab as a next generation CAR T cell with increased sensitivity,” Hanina further noted to GEN. “Unlike traditional CARs, which require a relatively high density of target molecules on the tumor cell surface to trigger killing, HIT T cells can recognize and eliminate tumor cells with much lower levels of antigen.”
The team showed in mouse and cell models that the CD70-HIT cells completely and durably eradicated tumors with mixed levels of CD70 expression across models of renal, ovarian, and pancreatic cancers. In contrast, conventional CAR T cells only eliminated a portion of cells. The HIT cells also stayed clear of healthy cells in the mice, since most other cells in the body do not express CD70 molecules.
“The HIT receptor works by co-opting the downstream signaling machinery of a T-cell receptor (TCR), which promotes the sensitivity,” Hanina continued. “This allows HIT T cells to detect even very low levels of CD70 on tumor cells—levels that traditional CAR T cells would typically miss … This is a novel approach, and the first report of a HIT receptor being applied in solid tumors.”
An epigenetic “signature” of low-level expression
Speaking to GEN, Hanina added, “By uncovering the mechanism by which CD70 was partially silenced but still expressed at low levels, we identified an epigenetic “signature” of low-level expression that is also present in patient tumors, supporting the potential applicability of HIT-based therapies.”
“Overall, our results demonstrate that CD70 target expression in CD70-heterogeneous tumors is pan-cellular, making a broad range of tumors therapeutically targetable provided a highly sensitive engineered CAR is used,” the investigators noted.
Hanina and Sadelain are now planning to test the CD70 HIT cells in patients with ovarian and other cancers at Columbia University Irving Medical Center. “We hope to undertake clinical studies in multiple cancer, including ovarian cancer, glioblastoma and others but are still seeking funding to perform this,” Hanina stated to GEN.
Potential utility against multiple tumor types
CD70 HIT cells may also have potential in nearly 20 other types of cancers, including glioblastoma and pancreatic adenocarcinoma, which are known to express CD70 to some degree. “Twenty or more solid tumor types express CD70 heterogeneously,” the authors noted in their paper. “Our works opens up the possibility that tumors comprising only a fraction of CD70-positive tumor cells may express CD70 in more tumor cells than identified by conventional staining methods, and may therefore be targeted by a sensitive immunotherapy such as CD70-HIT T cells.”
Though solid cancers present other obstacles to cell therapies, for cancers expressing CD70, the hunt for every cancer cell may be a critical obstacle to overcome. “Studies suggest that the escape of undetected cancer cells is the key impediment to therapeutic success with conventional CAR T therapy,” said Hanina. “We hope our CD70-directed HIT cells help us find a way to eradicate the entire tumor.” The authors concluded, “Our findings position CD70 as a pan-cancer target and provide a model for uncovering additional stealth targets amenable to sensitive immunotherapeutic approaches in the face of apparent tumor antigen heterogeneity.”
The post Ultra-Sensitive CAR T Cells May Unlock Potential Therapeutic Strategy for Solid Tumors appeared first on GEN – Genetic Engineering and Biotechnology News.
