RORing CAR T cells in solid and hematological cancers: same but different

Summary

A recent phase I clinical study tested anti-ROR1 CAR T cells in patients with CLL, NSCLC, and TNBC. The product could be safely administered and had activity in CLL but less so in NSCLC and TNBC.

In this issue of Clinical Cancer Research, Jaeger-Ruckstuhl and colleagues report on the results of their phase I clinical trial using anti-ROR1-targeted chimeric antigen receptor (CAR) T cells in patients suffering from hematological and solid tumors ¹. A total of 21 patients were included in the study and treated with escalating doses of anti-ROR1-CAR T cells with most patients ending up at the 3.3 x 10⁶/kg dose level. The treatment was reported to be safe with manageable conventional (cytokine release syndrome, CRS and immune cell associated neurotoxicities, ICAN) toxicities but also pulmonary toxicities at high frequencies (14/21 patients) not readily attributable to CAR T cell activity nor target expression. Activity was observed in patients suffering from chronic lymphocytic leukemia (CLL) with 2/3 patients responding with up to a transient complete remission. In the solid tumor cohort, which included patients suffering from non small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC), only a single transient partial response was described. 15/18 patients had short term stable disease, making up for a limited activity in this setting. Translational studies revealed a mixture of loss of ROR1 expression and insufficient CAR T cell expansion as potential reasons for failure of anti-ROR1-CAR T cells in CLL patients. In contrast, while expansion remained a problem to NSCLC and TNBC patients, this was attributed to a large extend to immunogenicity of anti-ROR1-CAR T cells in these settings, leading to their rapid elimination. Another key limitation was the poor infiltration of said CAR T cells into the patients respective tumor, as a factor restricting the activity of the cellular product.

Activity of CAR T cells in a number of hematological cancers is in stark contrast to what has been observed in solid tumors ². These differences have been attributed to a) the limited accessibility of solid tumor tissue for CAR T cells, which does not constitute a significant barrier in hematology; b) insufficient tumor cell recognition as a consequence of cancer heterogeneity and c) immune suppression dampening CAR T cell function³. These factors have however been identified by analogy across products and antigens, as most antigens and CAR cannot be readily transferred between hematology and solid cancers ⁴. Along these lines, limited activity may also equally source in product related constraints such as CAR design, CAR tonicity or lymphocyte fitness ⁵. By nature, such factors can vary widely between two products, even within the same cancer entity. This is where the Jaeger-Ruckstuhl study advances the field: for the first time the same CAR is being tested in both cancer categories. Importantly, anti-ROR1-CAR T cells have relevant activity in CLL but limited performance in NSCLC and TNBC, thus correcting for the key parameters of CAR and product variance in assessing comparative limitations. This unique situation enables direct comparison of potential disease-related parameters affecting CAR T cells performance and the differences are striking. While in CLL relapse was linked to antigen or T cell loss respectively, which could be anticipated from other CAR T cell studies in hematology, NSCLC and TNBC revealed infiltration and immunogenicity of CAR T cells as key mechanisms for a dismal activity. This sheds light on fundamental frame work differences between hematological and solid cancer patients. The first have underlying immune suppression either as a consequence of their disease or as a result of treatment history or both. In such settings, immunogenicity seem to be less of a concern and does not impact treatment, which is in line with findings on approved CAR T cells ⁶. However, solid cancer patients do not have such fundamental underlying immune suppression and are thus prone to immune responses against foreign antigens, as seen in the present CAR backbone leading to deletion of cells and preventing their activity. Similarly, CLL cells are readily available to CAR T cells in the periphery or in the bone marrow where anti-ROR1-CAR T cells could be found in relevant numbers. In contrast in NSCLC or TNBC which localize both as primary tumor and metastasis in organs and tissues, CAR T cells showed a limited ability to reach these sites and consequently were found only in low numbers.

The findings of this study have high relevance for CAR T cell development in solid tumors. They inform on the need to consider CAR immunogenicity as a key concern and will probably push the field further towards humanized or fully human receptors. Second, the results underscore the need for strategies enhancing CAR T cell infiltration into tissues (figure 1). In fact, this had previously been recognized by the Riddell lab and proposed to be solved with a modified lymphodepleting regimen, favoring recruitment through chemokine modulation ⁷. However, while the modified lymphodepletion was also applied here, it proved to be insufficient, calling for additional approaches. These may include chemokine receptor engineering for direct migration or intracompartemental delivery ⁴. It can be reasoned that because anti-ROR1-CAR T cells are in principle efficacious in patients, if the right settings and environment are given, anti-ROR1-CAR T cells could become a framework, where additional engineering or non-engineering strategies could be tested to advance efficacy. Whether or not these lessons will contribute to advancing anti-ROR1 CAR T cells or other products to clinical efficacy in solid tumors will need to be demonstrated in further studies.

Figure 1. Resistance mechanisms of anti-ROR1-CAR T cells in hematological and solid cancers.

Adapted from an image created in BioRender. Kobold, S. (2024) https://BioRender.com/d23r649