Background Manufactured RAPA-201 cell therapy products are enriched for central-memory, polarized to Th1/Tc1, and rendered immune checkpoint-deficient and homeostatic cytokine-responsive. RAPA-201 safely mediates multiple myeloma remissions when administered after lymphodepleting conditioning and induces remissions in solid tumor patients in the post-PD-(L)-1 setting using immune-sparing conditioning [carboplatin (CBCCA) plus paclitaxel (PTX)] (separate abstract submitted by Gutierrez et al, SITC 2023; clinicaltrials.gov, NCT05144698). This latter clinical translation was motivated in part by our finding, described herein, that RAPA-201 demonstrate resistance to CBCCA plus PTX.
Methods RAPA-201 were manufactured using one-week culture in temsirolimus- and IFN-α-containing media and tested for sensitivity to chemotherapy inhibition (temsirolimus, TEM; etoposide, VP-16; paclitaxel, PTX; carboplatin, CBCCA; and topotecan, TOPO; see table 1/figure 1: concentrations and exposure intervals). Peripheral blood mononuclear cells (PBMC) served as negative control whereas positive controls consisted of pancreatic cancer cells (MIA-PaCa-2 line) and lung cancer cell lines (NCI-H1975 and NCI-H820). Multidrug resistance (MDR) activity factor (MAF) values were determined by flow cytometry efflux assays (Abcam, ab294534).
Results Relative to MIA-PaCa-2, RAPA-201 had increased resistance to TEM (table 1, EXPT #1: 9.8% vs. 69.0% yield, respectively), VP-16 (16.3% vs. 82.8% yield), and PTX (0.0% vs. 55.2% yield) and similar resistance to CBCCA (205.6% vs. 103.4% yield). Similar results were obtained in a second experiment (table 1, EXPT #2). Relative to PBMC, RAPA-201 had increased resistance to combination CBCCA + PTX (table 1, EXPT #1: 29.7% vs. 61.7% yield; EXPT #2: 63.4% vs. 138.2% yield). Relative to cellular controls (NCI-H1975, NCI-H820, PBMC), RAPA-201 had increased topotecan resistance (figure 1). MDR activity was not detected in control PBMC (MAF score, 0); in contrast, in two separate experiments, RAPA-201 had functional MDR activity for MDR1 (median MAF: 5.2, 15.9), MRP1/2 (median MAF: 6.1, 24.7), and BCRP (median MAF: 8.7, 8.2).
Conclusions RAPA-201 are globally resistant to numerous chemotherapy agents, including carboplatin, paclitaxel, temsirolimus, etoposide, and topotecan. The mechanism of RAPA-201 resistance may involve MDR activity; however, as we have previously demonstrated, modulation of intrinsic apoptotic signals is also likely operational. It is important to harness RAPA-201 chemotherapy resistance for clinical translation, as we have now successfully achieved through use of CBCCA/PTX immune-sparing conditioning to safely facilitate RAPA-201 regression of post-PD-(L)1 solid tumors. Finally, given RAPA-201 resistance to topotecan, which is in the topoisomerase I drug class commonly utilized as payload for antibody-drug-conjugates (ADC), it will be important to clinically translate combination therapy involving RAPA-201 and ADC agents.
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