The researchers pointed out that autologous TILs have mediated substantial objective tumor regressions in patients with other forms of cancer, including metastatic bile duct, colon, and cervical cancers. Dr Rosenberg has conducted pioneering research with TIL therapy for more than 20 years, beginning with in vitro and murine tests before targeting metastatic melanoma in a clinical trial that ran from 1987 to 1992.4

Since then, as a group of Dutch and Danish researchers remarked in a 2015 paper, a series of additional phase 1 and 2 clinical trials have “convincingly shown that TILs selected for reactivity towards autologous melanoma cells displayed high functional activity in metastatic melanoma patients, with [objective response rate] varying between 34% and 72% of treated patients some of whom developed a long-lasting complete remission …”5


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In a 2004 article, Dr Rosenberg theorized that “the success of this treatment likely results from the ability to infuse large numbers of activated antitumor lymphocytes into an appropriate host homeostatic environment depleted of regulatory T cells.”6

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Since then, the understanding of the working mechanism has grown substantially, the authors of the 2015 paper stated, “especially regarding the role of lymphodepleting conditioning of the host, the role of interleukin-2 as a survival factor for the infused TIL, the optimal quality and quantity of the infused cells and their antigen recognition pattern.”5

In addition, Dr Rosenberg explained in an overview of adoptive cell transfer therapy (ACT) in 2015, the ability to genetically engineer lymphocytes has expanded the successful range of application of the treatment.7

But, he commented, “A major factor limiting the successful use of ACT in humans is the identification of cells that can target antigens selectively expressed on the cancer and not on essential normal tissues.”7

Therefore, he said, “The continued development of ACT, as well as other immunologic approaches to the treatment of cancer, depends on the identification of suitable targets for immunologic attack. Although CARs have been successful in the treatment of hematologic malignancies and are likely to soon join the mainstream of oncologic treatment, the ability to treat common epithelial solid cancers, which account for ~90% of all cancer fatalities, is severely limited by the lack of suitable targets exclusive to cancer.”7

Still, for most cancers, TILs offer a valuable prognostic or diagnostic function. In fact, the Dutch writers continued, “the presence of TILs and its association with improved survival has been documented in virtually every human cancer studied.”5

Such has been true of breast cancer, until recently. 

As the writers of a 2017 review described, TILs are one of the best examples of the strict relationship that exists between natural defenses and carcinogenesis and represent a snapshot of the tumor scenario. … In parallel, the clinical evaluation of tumor-infiltrating lymphocytes has been shown to effectively predict treatment outcomes in both neoadjuvant and adjuvant settings.”8

Yet another possibility would be to harness the highly individualized nature of TILs in a broader, and more potent, therapeutic capacity, the review’s lead author, Andrea Ravelli, a PhD candidate in experimental oncology at the University of Parma in Italy, and visiting PhD student in the melanoma medical oncology department at the University of Texas MD Anderson Cancer Center in Houston, said in a telephone interview with Cancer Therapy Advisor.

“It seems like science fiction, but one of the implications of screening tumors both immunogenic and not is the individuation of some shared antigens that are able to trigger autologous reactivity in a harmless fashion that could, in the future, drive the setting up of some kind of antitumor vaccine — which would actually be the most futuristic option,” he said. “That’s actually where the study of TILs, alongside with other immune-related therapeutic approaches, are going toward … but before that step there’s still a lot of work to do.”

References

  1. Zacharakis N, Chinnasamy H, Black M, et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancerNat Med.2018;24(6):724-730. doi: 10.1038/s41591-018-0040-8
  2. National Institutes of Health. New approach to immunotherapy leads to complete response in breast cancer patient unresponsive to other treatments.https://www.nih.gov/news-events/news-releases/new-approach-immunotherapy-leads-complete-response-breast-cancer-patient-unresponsive-other-treatments. Updated June 4, 2018. Accessed July 27, 2018.
  3. ClinicalTrials.gov. Immunotherapy Using Tumor-Infiltrating Lymphocytes for Patients With Metastatic Cancer. NCT01174121. https://clinicaltrials.gov/ct2/show/NCT01174121. Accessed July 27, 2018.
  4. Rosenberg SA, Yannelli JR, Yang JC, et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2J Natl Cancer Inst. 1994;86(15):1159-1166.
  5. Geukes Foppen MH, Donia M, Svane IM, et al. Tumor‐infiltrating lymphocytes for the treatment of metastatic cancer [published online October 30, 2015]. Mol Oncol. 2015;9(10):1918-1935. doi: 10.1016/j.molonc.2015.10.018
  6. Rosenberg SA, Dudley ME. Cancer regression in patients with metastatic melanoma after the transfer of autologous antitumor lymphocytesProc Natl Acad Sci U S A. 2004;101(suppl 2):14639-14645.
  7. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancerScience. 2015:348(6230):62-68. doi: 10.1126/science.aaa4967
  8. Ravelli A, Roviello G, Cretella D, et al. Tumor-infiltrating lymphocytes and breast cancer: Beyond the prognostic and predictive utilityTumour Biol. 2017;39(4):1010428317695023. doi: 10.1177/1010428317695023