ABSTRACT
CAR T-cell therapy has transformed the treatment of hematological malignancies of the B cell lineage. However, the quest to fulfil the same promise for solid tumors is still in its infancy. This review summarizes some of the challenges that the field is trying to overcome for effective treatment of human carcinomas, including tumor heterogeneity, the paucity of truly tumor-specific targets, immunosuppression and metabolic restrictions at solid tumor beds, and defective T-cell trafficking. All these barriers are being currently investigated and, in some cases, targeted, by multiple independent groups. With clinical interventions against multiple human malignancies and different platforms under accelerated clinical development, the next few years will see an array of cellular therapies, including CAR T-cells, progressively becoming routine interventions to eliminate currently incurable diseases, as it happened with some hematological malignancies.
Chimeric antigen receptor (CAR) T-cells are T cells genetically engineered to express a targeting domain, typically derived from a monoclonal antibody, and intracellular signaling domains that promote cytotoxic killing of tumor cells upon specific antigen recognition. CAR T-cells have revolutionized the management of hematological malignancies, including lymphomas (Locke et al. Citation2022; Neelapu et al. Citation2017, Citation2022), leukemias (Grupp et al. Citation2013; Porter et al. Citation2011), and multiple myelomas (Raje et al. Citation2019). However, CAR T-cells have been largely unsuccessful thus far against solid tumors, including the most frequent and aggressive carcinomas. Major research efforts are being conducted to overcome the challenges that CAR T-cells encounter at solid tumor beds for anti-tumor activity. Those include strong immunosuppressive networks and abrasive metabolic restrictions, which could be ameliorated through genetic engineering of CAR T-cells. They also include the paucity of known targets that are not shared by vital tissues, which prevents the use of these superior, genetically engineered T-cells, to avoid life-threatening on-target, off-tumor toxicities. Differences between liquid and solid tumors also include reliance of the latter on IFNγR signaling for CAR T-cell susceptibility (Larson et al. Citation2022). Finally, antigen loss through tumor evolution could be accelerated in solid tumors, compared to hematological malignancies. This review will provide an update on ongoing clinical trials using CAR T-cells to treat solid tumors, along with emerging approaches to render cell therapies in general, and CAR T-cells in particular, effective against the most frequent and aggressive human malignancies.
The quest for solid tumor-specific antigens
The first barrier for effective CAR T-cell-mediated targeting of solid tumors is finding antigens that are expressed on the tumor cell surface but not in vital tissues, such as the lung or the heart. The success of CAR T-cells targeting CD19 is partially due to the fact that CD19 is not expressed in any vital organs or vital cells. CD19 CAR T-cells eliminate healthy B cells, but patients can live with immunoglobulin replacement. A list of CAR T-cell targets and associated solid tumors in clinical trials currently recruiting patients in the US is summarized in . As obvious from this list, most CAR T-cell targets are not tumor-specific.
Table 1. Current CAR T-cell targets and associated diseases in clinical trials currently recruiting patients with solid tumors in the US (clinicaltrials.Gov; 23 June 2022).
In an effort to target a tumor-specific antigen, Maus and colleagues generated CAR T-cells against the epidermal growth factor receptor variant III (EGFRvIII) mutation in a seminal study (O’Rourke et al. Citation2017). Interventions in 10 patients were safe, without evidence of off-tumor toxicity or cytokine release syndrome. At least one patient had evidence of sustained residual stable disease. However, enhanced immuno-inhibitory mechanisms after CART-EGFRvIII infusion were observed in most patients, further underscoring the need to generate CAR T-cells that can overcome adaptive changes in the tumor milieu. Nevertheless, even in the case of rapid antigen loss through tumor adaptation, CAR T-cells could have a sustained effect through activation of pre-existing, endogenous, polyclonal anti-tumor immunity, as evidenced in mouse models in different systems (Avanzi et al. Citation2018; Perales-Puchalt et al. Citation2017).
Another open basket trial is currently targeting the tumor-associated MUC1 glycopeptide epitopes first reported by Olja Finn (Keane and Posey Citation2021; Ryan et al. Citation2009), the expression of which is primarily restricted to tumor cells. These first-in-human interventions focus on patients with advanced TnMUC1-Positive solid tumors, as well as multiple myeloma (NCT04025216). In this approach, tumor specificity is provided by aberrant glycosylation of MUC1 in tumor cells, which distinguishes tumor-associated TnMUC1 from normal MUC1. Similar approaches targeting glycoantigens in ovarian cancer patients (Murad et al. Citation2018) are currently being tested at City of Hope (NCT05225363). Glycoantigens could therefore offer a form of tumor specificity for proteins that are otherwise expressed in healthy tissues.
In another ongoing clinical trial (NCT05316129), a team at Moffitt Cancer Center is targeting for the first time the FSH Receptor in patients with recurrent, ovarian cancer progressing after cisplatin therapy. Previous studies could not find expression of the FSHR target in any vital tissue through Q-PCR analyses, including in the brain, the heart, the lung or the liver (Perales-Puchalt et al. Citation2017). Similarly, in vivo studies in mice sing CAR T-cells that target the murine FSHR showed therapeutic effectiveness in the absence of any measurable toxicity (Perales-Puchalt et al. Citation2017). Although these studies are still ongoing, they could provide support for novel targets that prime specificity over expression levels, given than not more than 200 copies of the target per cell are sufficient for cytotoxic killing by at least some CAR T-cells (Watanabe et al. Citation2015). In this trial, the targeting motif consists of the two subunits of FSH (Perales-Puchalt et al. Citation2017), as opposed to the heavy and light chains of an antibody that are typically used in other CAR T-cells.
Other targets under preclinical development that lack expression in vital tissues rather than being expressed at high levels in tumor cells include a set of olfactory receptors, some of which (i.e., OR2H1) have shown promise in humanized mouse models (Martin et al. Citation2022). Some of these targets are now pursued for clinical testing. Given the feasibility of genetic ablation of genes that counteract T cell effector activity, such as PD-1 (Stadtmauer et al. Citation2020), CAR T-cells could be engineered to better resist immunosuppressive networks at tumor beds, thus multiplying their effector activity. Furthermore, Mansilla-Soto and colleagues recently engineered novel HLA-independent T cell receptors (HIT receptors) that mediate superior recognition of antigens expressed at very low abundance, through a TCR complex reconfigured to utilize the same immunoglobulin heavy and light chains of a CAR (Mansilla-Soto et al. Citation2022). Although the authors integrated this HIT construct into the TRCA locus, the same approach can be used through lentiviral or retroviral transduction of the construct. The bottom line of these approaches is that enhanced sensitivity and resistance to immunosuppression and metabolic restrictions can be achieved in multiple ways, provided that the target is not expressed in tissues and cells required for a healthy life; even if those expression levels are low. Specificity therefore could be more important than abundance, as illustrated below.
Targets expressed at higher levels in tumor cells, compared to vital tissues
The paucity of specific targets accessible on the tumor cell surface has led to an array of CAR T-cell interventions against targets such as mesothelin, despite expression in vital tissues, such as pericardium, pleura or the peritoneal lining. Mesothelin is overexpressed in ovarian, pancreatic and lung cancer, among other tumors. Despite broad expression beyond tumor cells, regional delivery of CAR T-cell therapy can theoretically provide a layer of safety, according to a recent clinical trial (Adusumilli et al. Citation2021). These interventions allowed combination with Pembrolizumab and demonstrated some antitumor efficacy in patients with malignant pleural diseases. However, after the publication of the results of this initial trial, a dose-escalation CAR T-cell trial in patients with mesothelioma at the same institution (NCT04577326) had to be put on hold, following a patient death. These results underscore the potential of fine-tuned CAR T cells targeting antigens overexpressed in cancer, even if they are also expressed in vital tissues. However, they also evidence the limitations and risks of shared targets, for which “super-T-cells” engineered to overcome tumor-induced immunosuppression would likely result in fatal toxicities.
Another trial has been recently open at UNC Lineberger Cancer Center to test B7-H3 CAR T cell administration in patients with relapsed or refractory glioblastoma (NCT05366179), with a parallel trial targeting B7-H3 in ovarian cancer patients (NCT04670068). Relatively high expression in multiple cancers make B7-H3 a very interesting target for CAR T-cell immunotherapy (Du et al. Citation2019). A potential concern, however, is that while translation of B7-H3 mRNA is prevented in the steady state, B7-H3 mRNA is detected in many normal tissues, including coronary arteries, nerves, and the digestive tract, according to GTEX. B7-H3 protein expression could therefore theoretically appear in vital tissues under conditions of inflammation. These important ongoing trials will soon define the potential of B7-H3 as an immunotherapeutic target and the safety of these interventions.
Besides on-target, off-tumor specific effects, another potential risk of CAR T-cells when used against solid tumors could be massive macrophage activation syndrome. Thus, a recent CAR T cell trial targeting PSMA with TGF-β-resistant lymphocytes (NCT04227275) also had to be put on hold when two patients underwent lethal neurotoxicity. Although, according to GTEX and other public databases, PSMA is expressed in the brain, it is unclear whether CAR T-cells could have crossed the blood–brain barrier, which makes learning how to monitor and promptly target cytokine release in patients receiving similar interventions crucial for the future of the field.
Other targets undergoing clinical testing or recently evaluated targets that are co-expressed in vital tissues but have shown acceptable toxicity so far include folate receptor alpha (overexpressed in healthy lung), which is being targeted in ovarian cancer patients (NCT03585764); ROR1, expressed in coronary arteries, according to GTEX, and targeted in patients with both solid and liquid tumors (although terminated due to slow accrual; NCT02706392); and MUC16, expressed in the lung and multiple other tissues, and targeted with CAR T-cells in patients with multiple solid tumors (NCT02498912). Besides, HER-2, expressed in the esophagus, nerves, and multiple arteries has been the target of multiple interventions using CAR T-cells. Pulmonary toxicity occurred in the first patient treated with HER-2 targeting CAR T-cells, likely because of low expression level in lung epithelial cells (Morgan et al. Citation2010). Finally, different NKG2D-based CAR T-cells, pioneered by Charles Sentman (Barber et al. Citation2007) are undergoing clinical testing against a variety of diseases (Curio et al. Citation2021). Ligands for NKG2D are expressed on cancerous or stressed cells and are absent from healthy tissue in the steady state, although they can be turned-on during, for instance, inflammatory conditions. Preliminary data from these clinical trials are promising (Curio et al. Citation2021), and further research is being developed to enhance effectiveness and safety. Together, ongoing clinical evidence suggest that non-specific targets could indeed benefit a fraction of patients if they are carefully selected and managed, but also emphasizes the risks of cellular therapies without tumor-specific targets and call for alternative targets or engineering approaches to minimize these risks. The field clearly needs a comprehensive analysis of Proteogenomic datasets from multiple tumors to identify antigens with a GPI-anchored or transmembrane domain that could be expressed by tissues, such as testis or the ovary, but not truly vital organs. This approach will require accompanying methods to identify tumors truly expressing the target, as positivity will likely be restricted to a fraction of patients. It is becoming increasingly clear that solid tumors will not be targeted by the equivalent of a CD19 CAR in B cell malignancies.
Local CAR T-cell administration or systemic delivery?
As aforementioned, some of the risks associated with on-target, off-tumor activity could be nevertheless reduced by local infusion of CAR T-cells into the tumor microenvironment (TME), while increasing CAR T-cell accumulation at tumor beds and bypassing issues of T-cell trafficking. For example, CAR T cells targeting disialoganglioside GD2, frequently overexpressed in H3K27 M-mutated diffuse midline gliomas and expressed in multiple healthy tissues, have demonstrated promising clinical efficacy in four patients enrolled in a first-in-human clinical trial (Majzner et al. Citation2022). In this trial, patients who experienced clinical benefit after I.V. administration of CAR T cells subsequently received GD2-CAR T cell infusions administered intracerebroventricularly, with local and manageable toxicities. Three of these patients showed objective clinical improvement.
In ovarian cancer, CAR T-cells targeting the Folate Receptor Alpha have been administered intraperitoneally (NCT03585764), which also concentrates CAR T-cells in the vicinity of tumor cells and bypasses limitations of T-cell trafficking to the TME. It is unclear, though, whether intraperitoneal administration in pre-treated patients with recurrent ovarian cancer ensures uniform distribution of CAR T-cells through adhesions in the peritoneal space. This is a challenge for intraperitoneal chemotherapy of this disease that the field is currently trying to address in multiple ways (Ceelen et al. Citation2020). To ensure better biodistribution, combined intravenous and intraperitoneal administration of CAR T-cells targeting MUC16 and secreting IL-12 have been recently tested, following schedules optimized for chemotherapy (NCT02498912). In addition, the ongoing trial targeting FSHR+ ovarian cancer aims to solve that question by comparing effectiveness in patients receiving intraperitoneal vs. intravenous CAR T-cells (NCT05316129). A similar question emerges for pleural or even bronchial malignancies, as regional delivery of anti-mesothelin CAR T-cells has shown some effectiveness (Adusumilli et al. Citation2021). The optimal route of CAR T-cell administration for each disease is a crucial issue that needs to be dissected by the field before cellular therapies can become a standard of care for cancer treatment. The disease for which this question is having a concerted answer so far is glioblastoma, because systemic intravenous administration of CAR T-cells results in limited CAR T-cell infiltration, due to the challenge of crossing the blood–brain barrier (Maggs et al. Citation2021). Accordingly, most ongoing CAR T-cell trials include local adoptive transfer. The obvious concern of this approach is neurotoxicity, which can occur independently or in conjunction with cytokine release.
Engineering CAR T-cells to overcome the tumor microenvironment
Unlike CAR T-cells administered to treat liquid tumors, CAR T-cells encounter multiple challenges to exert their effector activity in solid tumors. Those include metabolic restrictions, with limited glucose availability, along with multiple immunosuppressive networks generated in the TME by co-opting immune checkpoint inhibitory pathways. In addition, effective trafficking to tumor beds and possible sequestration in stromal compartments represent additional challenges for cellular therapies, compared to the treatment of most hematological malignancies. As the field evolves and identifies safe targets for CAR T-cell interventions, multiple complementary approaches to overcome these limitations are being intensely investigated. As aforementioned, for instance, pioneering clinical interventions by Carl June and colleagues demonstrated the safety and feasibility of genetically ablating genes that counteract T cell effector activity, such as PD-1, using the CRISPR-CAS system (Stadtmauer et al. Citation2020). This seminal clinical trial opens the door to the testing of CAR T-cells engineered in multiple ways to better resist immunosuppressive networks at tumor beds. For instance, drivers of T-cell inhibition that emerge as obvious targets for CRISPR-mediated ablation include immuno-inhibitory mediators of ER stress, such as PERK or XBP1, both of which paralyze T-cell effector activity at tumor beds (Cao et al. Citation2019; Song et al. Citation2018), and do not have effective and safe clinical inhibitors.
To overcome inhibition of adoptively transferred T cells in a hostile TME, Brentjens and colleagues followed a different approach by engineering “armored” CAR T-cells that secrete IL-12 (Yeku et al. Citation2017). The approach has been refined to express other cytokines, as well as antibody fragments, and could provide a platform to enhance effector CAR T-cell activity while boosting pre-existing anti-tumor immunity, in vivo and in situ at tumor beds.
Different groups are also investigating the ectopic expression of different chemokine receptors that respond to chemokines frequently overexpressed at tumor beds, with the goal of overcoming low CAR T-cell trafficking to the tumor microenvironment. For instance, expression of CCR8 in CAR T-cells resistant to TGF-β, has shown some promise in preclinical models (Cadilha et al. Citation2021). In addition, different active clinical trials are using CAR T-cells transduced with CXCR2 (NCT01740557) or CCR4 (NCT03602157), to improve trafficking of T cells to hematological and skin tumor sites.
Newly developed “SNIP CARs,” which depend on the inhibition of a protease-based platform through the administration of an FDA-approved drug for effectiveness, offer new possibilities for a possible safety switch. Equally important, SNIP CARs have shown more potent activity, decreased exhaustion, and enhanced stemness, compared to regular CAR T-cells, in different in vivo models (Labanieh et al. Citation2022).
Another approach to enhance the effectiveness of CAR T-cells at tumor beds, recently reported by Serge Fuchs and colleagues, is based on targeting of PARP11, which is induced in intratumoral T-cells and governs downregulation of IFNAR1 in response to the activity of regulatory T cells and adenosine (Zhang et al. Citation2022). PARP11 can be pharmacologically inhibited, or CAR T-cells can be engineered to inactivate PARP11, resulting in enhanced anti-tumor activity in preclinical models.
Engineering CAR T-cells for enhanced specificity and overcoming tumor heterogeneity
Special mention deserves the development of safer fine-tuned CAR T cells that only effectively recognize tumor cells that express higher levels of target antigen. Thus, in a recent study, Hernandez-Lopez and colleagues developed fine-tuned CAR T-cells that distinguish antigen-expressing cells with high vs. low density (Hernandez-Lopez et al. Citation2021). This “two-step recognition circuit” is based on a synNotch-controlled gene expression system in which a low-affinity CAR recognizes HER-2 with low affinity, thus signaling only upon recognition of tumor cells with high, but not low, levels of HER-2. This induces the expression of a high affinity HER-2-specific CAR on the T-cell surface. Increasing HER2 density thus increases CAR expression in T-cells, leading to a sigmoidal response. Using this system, target cells expressing normal amounts of HER2 and cancer cells expressing higher levels can be effectively discriminated. This system, applicable to other targets expressed at low levels in vital organs, could help prevent the fatalities observed in some initial trials, and open an array of targets that could be shared by vital tissues, but with low expression levels.
On the other hand, to limit antigen escape, multiple approaches based on split, dual CAR T-cell targeting have been developed in recent years, mostly against hematological malignancies. In these constructs, a targeting motif is typically linked to a co-stimulatory signaling domain, while the other is linked to CD3ζ. This approach also appears to enhance metabolic fitness in preclinical models of solid cancer (Hirabayashi et al. Citation2021). Dual targeting could also overcome the issue of heterogeneous expression of a specific target, although the limitations associated with on-target, off-tumor effects apply to both targeting motifs. Finally, it is tempting to speculate that low affinity targeting motifs could also enable CAR T-cells that recognize tumor cells expressing both targets at higher levels than healthy cells, which would ideally express only one of them.
CAR T-cells, but what T-cells?
The aforementioned CAR T-cell interventions are based on retroviral or lentiviral transduction of MHC-restricted αβ T cells. However, there are other immune cells, such as macrophages (Klichinsky et al. Citation2020) and NK cells (Liu et al. Citation2020) that have been safely used to express chimeric receptors, including in clinical trials (NCT04660929, NCT03056339). In addition, different T-cell subsets are being developed as CAR T-cell platforms. Among them, NKT cells offer an attractive dual innate and adaptive immune activity. In a recent trial, Metelitsa and colleagues demonstrated that CAR-NKT cells can be expanded to clinical scale, and used to safely treat patients with neuroblastoma, using GD2 as a targeting motif (Heczey et al. Citation2020). Equally important, CAR-NKT cells trafficked to bone metastases and elicited the regression of relapsed/refractory neuroblastomas. These studies open new avenues for unconventional T-cell subsets to be used as platforms for CAR expression, as they can combine additional MHC-independent anti-tumor activity, homing to tumor beds and even metabolic superiority.
Another promising T-cell subset with all these features could be γδ T cells, and in particular Vδ1 lymphocytes. γδ T cells, which express a unique TCR with a γ and a δ chain, represent <5% total T cells, but are enriched in epithelial tissues. In humans, most γδ T cells in tissues are Vδ1 T cells, while in peripheral blood the dominant population is composed by Vδ2 lymphocytes (Di Marco Barros et al. Citation2016; Fleming et al. Citation2017; Suzuki et al. Citation2020). However, the small subset of circulating Vδ1 T-cells can be expanded to clinical scale (Makkouk et al. Citation2021), which is important for CAR T-cell allogeneic approaches. Importantly, Vδ1 T cells are also predominant in lung (Wu et al. Citation2022), ovarian (Payne et al. Citation2020), and live cancer (Zakeri et al. Citation2022). In all cases, an association between γδ T cell infiltration and improved outcome has been reported. Vδ1 T cells could therefore home to tumor beds more effectively and exert additional cytotoxic activity independently of the CAR (for instance, through NKG2D). The potential of γδ T cells as CAR vectors has been further underscored by a recent study from Carl June showing that, in a long-term survivor after receiving CD19 CAR T-cell therapy, the predominant population of T-cells expressing the CAR after >1 year were γδ T-cells (Melenhorst et al. Citation2022). γδ lymphocytes therefore have the capacity to persist and exert sustained immune pressure against malignant progression and could offer numerous advantages over conventional αβ T cells, including their use in an allogeneic setting. Other preclinical interventions, using peripheral Vγ2 CAR T cells in combination with zoledronate, are being optimized at Moffitt for targeting bone metastases in patients with prostate cancer, pointing to another lymphocyte subset that could be used for preferential targeting of bone malignancies.
Concluding remarks
Recent years have seen an array of CAR T-cell-based clinical interventions to treat solid tumors, many of which are still active and should provide valuable insight into the potential and barriers for this approach. Compared to the management of malignancies of the B cell lineage, CAR T-cells have been largely infective so far against epithelial tumors. Major challenges include the paucity of accessible targets not expressed in healthy tissues, T-cell trafficking, and an immunosuppressive and metabolically restricted milieu that prevents T-cell activity. Multiple interventions to overcome CAR T-cell dysfunction and enhance tumor-specificity and therefore safety are being developed in preclinical systems, and some of them are undergoing clinical evaluation. Given intense clinical activity in the setting of prostate, ovarian, and pancreatic cancer, as well as mesothelioma, glioblastoma, and melanoma, the field is expected to overcome some of these barriers and technical challenges in relatively short time, thus fulfilling the promise of cellular therapies for the cure of patients with the most frequent and aggressive forms of cancer, besides hematological malignancies.
Disclosure statement
JRCG has stock options in Compass Therapeutics, Anixa Biosciences, and Alloy Therapeutics; has sponsored research with Anixa Biosciences; receives honorarium from Alloy Therapeutics and Leidos; and has intellectual property with Compass Therapeutics and Anixa Biosciences.
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References
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