You Complete Me

Jun 28, 2023

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One of the most quotable movies of all time is Jerry Maguire. The plot centers on the unintentional journey of an ultra-slick sports agent starring Tom Cruise that puts aside his cynicism and resets his moral compass at great cost to himself both personally and professionally. Alongside iconic lines from the movie like “Show me the money!”, “You had me at hello”, and “Help me help you” (and who could forget those?) is the perfectly placed, “You complete me”, which lands with maximum emotional impact as Jerry works the room, holding forth in a den of divorced, misandrous women to win back his wife Dorothy Boyd, played by Renée Zellweger. This climactic scene occurs after much soul searching and hilarious banter with Cuba Gooding Jr.’s Rod Tidwell, in which Jerry comes to the poignant realization that his wife, Dorothy, who initially he married more out of pragmatism and fear of loneliness than true love, completes him.

Like Jerry Maguire, immune checkpoint inhibitors (ICIs) are incomplete without a perfect Renée Zellweger-like “partner” that will help them to overcome resistance and to sensitize all solid tumors, not just already immune-susceptible ones like non-small cell lung cancer (NSCLC), urothelial cancer, renal cell carcinoma (RCC) and melanoma. ICIs have revolutionized the treatment of cancer, but only for a select few. Sad to say, most patients, especially those with “cold” tumors like microsatellite stable colorectal cancer, ovarian cancer, pancreatic cancer, and prostate cancer, where immune T-cells are absent or suppressed, do not benefit from ICIs.

An array of combination partners has been tried with ICIs by and large unsuccessfully including other ICIs, chemotherapies, oncolytic viruses, tumor vaccines, targeted therapies, CAR-Ts, and radiation, for the most part because these agents have added toxicity with only incremental or no clinical benefit.

A hallmark of the EpicentRx therapies, RRx-001 and AdAPT-001, is their tolerability; to date, both have been administered to patients in the absence of any dose-limiting toxicities as single agents and in combination. Also, both have demonstrated potential evidence of activity in cancer. This augurs well for their future as ICI partners. In a 12-patient clinical called PRIMETIME (click here to read the published manuscript entitled, Phase 1 pilot study of RRx-001 + nivolumab in patients with advanced metastatic cancer (PRIMETIME)) the addition of RRx-001 to nivolumab, a so-called PD-1 immune checkpoint inhibitor, led to a 25% objective response rate in tumor types that are traditionally resistant to ICIs.

For its part, AdAPT-001 carries a transforming growth factor beta (TGF-β) trap that sequesters and neutralizes the protein, TGF-β, which most tumors overexpress to their advantage. This is because among its many harmful properties in cancer TGF-β lowers anti-tumor immunity. Preliminary data from an ongoing Phase 2 trial called BETA TRAP indicate that the combination of AdAPT-001 + a checkpoint inhibitor is not only well-tolerated with no related serious adverse events (SAEs) but also active, which is unexpected from the perspective that these patients have already previously received and failed ICIs.

So, let’s close with another Jerry Maguire quote, which also applies to the business of drug development: “we live in a cynical world, a cynical world, and we work in a business of tough competitors.” (Yes, exactly, Jerry, and, for the record, you had us at “cynical”.) Well, that said, it is just possible that either RRx-001 and/or AdAPT-001 from EpicentRx will serve as the missing pieces that complete immune checkpoint inhibitors and make them more active for the good of all cancer patients, and not just a subset of them.