Getting Complex Therapies to More People: A Vexing Dilemma

Author: Margaret Tempero MD
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Today I am enjoying a light schedule with few meetings on my calendar, so I had the chance to rifle through the pile of journals cluttering my desk. On top was the latest issue of the Journal of Clinical Oncology, which included a provocative article detailing the interim results of a phase II clinical trial in metastatic breast cancer using mutation-reactive autologous lymphocytes.1 But before I dive into the issues that flooded my brain as I read it, let me tell you a little about the group that did the work.

The study comes from the Surgery Branch of the NCI, which is led by one of my heroes, Steven Rosenberg, MD, PhD, who has been there as long as I can remember. He has been a pioneer in advancing cellular therapies and is assisted by a brilliant army of immunology scientists, including other physicians. I have followed their work for years—work that arguably could only happen at an institution like the NCI. Why do I think this? The therapies they develop are complex, and the studies appear to have no external sponsor. Thus, every step is internally funded.

But back to the paper. In this trial, which has been open for several years, tumor-infiltrating lymphocytes were harvested and tested for robust reactivity against neoantigens found in the matching tumor sample. Once qualified, the lymphocytes and pembrolizumab were administered. Of 6 patients treated, 3 showed response, including 1 complete response that has been durable. Clearly, in some cases, a person’s own cells can be trained to turn against the tumor.

So, what bothers me? Well, the trial included 42 patients who obviously were chosen based on selective eligibility characteristics. Of the cohort, only 28 had tumor-infiltrating lymphocytes that recognized at least one somatic mutation. Of these 28 patients, only 13 had reactivity robust enough for adoptive transfer. Of these 13, only 8 remained clinically eligible, and 6 were treated. Using an intent-to-treat analysis, this translates to a response rate of approximately 7%. With results like this, would a pharmaceutical company be interested in furthering this treatment?

I would argue that this work is promising and that we just need a more efficient process to select patients who have a chance to benefit. I have no doubt that Dr. Rosenberg and his team feel the same way. It needs to be something simple, such as a biomarker easily identified in existing tumor tissue. Patients in need of investigational therapy need a fast answer about whether or not they meet eligibility criteria. And then we need to be prepared to offer specialized cellular therapies through some sort of network so that these are available to all eligible patients, not just those willing to travel to the NCI.

Of course, the gorilla in the room is still there: this will cost a lot of money. But let’s not get hung up on that now. If the therapy is transformative, whatever it costs is worth it.

Reference

1.

Zacharakis N, Huq LM, Seitter SJ, et al. Breast cancers are immunogenic: immunologic analyses and a phase II pilot clinical trial using mutation-reactive autologous lymphocytes [published online February 01, 2022]. J Clin Oncol, doi: 10.1200/JCO.21.02170

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MARGARET TEMPERO, MD

Margaret Tempero, MD, is a Professor of Medicine and Director of the UCSF Pancreas Center and editor-in-chief of JNCCN. Her research career has focused on pancreatic ductal adenocarcinoma, especially in the area of investigational therapeutics. Dr. Tempero has served on the ASCO Board of Directors and as ASCO President. She currently serves on the ASCO Conquer Cancer Foundation Board. She codirected the AACR/ASCO Methods in Clinical Cancer Research and taught this course and similar courses in Europe and Australia. She was founding Chair of the NCI Clinical Oncology Study Section and served as a member and Chair of the NCI Board of Scientific Counselors Subcommittee A. She is a member of the Scientific Steering Committee and Chair of the Clinical and Translational Study Section for the Cancer Prevention & Research Institute of Texas. She is or has been on the Scientific Advisory Boards of the Lustgarten Foundation, the Pancreatic Cancer Action Network, the V Foundation, The Alberta Canada Cancer Board, and the EORTC. She served as a member of the Oncology Drug Advisory Committee for the FDA. She has served as Deputy Director and Interim Director for the UNMC Eppley Cancer Center. She is Chief Emeritus of the Division of Medical Oncology at UCSF. She served as the founding Deputy Director and was later Director of Research Programs at the UCSF Helen Diller Family Comprehensive Cancer Center.

  • 1.

    Zacharakis N, Huq LM, Seitter SJ, et al. Breast cancers are immunogenic: immunologic analyses and a phase II pilot clinical trial using mutation-reactive autologous lymphocytes [published online February 01, 2022]. J Clin Oncol, doi: 10.1200/JCO.21.02170

    • Search Google Scholar
    • Export Citation
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