Applying dosing schedules to the clinical protocols of combinatorial therapy


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Applying dosing schedules to the clinical protocols of combinatorial therapy

  1. 1. Applying dosing schedules to the clinical protocols of combinatorialtherapy, we can optimize the clinical outcome 4-14-2010In 1986, a clinical protocol for the treatment of advanced malignant melanoma withthe newly discovered class of immune cells called TIL was initiated at the NationalInstitutes of Health (NIH). These lymphocytes are T cells that are isolated directly fromthe tumor and that are then grown to large numbers in tissue culture in the presence of theT cell growth factor interleukin-2 (IL2). After expansion in culture several thousandtimes, approximately 2 X 10" TIL are given to the patient intravenously in addition tohigh doses of IL-2 in several days of treatment. Even in those patients who did notrespond to all other therapy (including treatment with IL-2 alone), 35 to 40% of patientsresponded to this protocol.The large-scale tissue culture and the large numbers of cells and IL-2 that are given to apatient make this procedure expensive and clinically difficult. Furthermore, 60 to 65% ofpatients fail to respond to this treatment, and even those who do respond will often failafter 6 to 12 months. It is likely that only a subset of the heterologous population of cellsadministered to a patient are effective in killing cancer cells in vivo.That was then (1986) and this is now 2009. Dr. Rosenberg and colleagues have optimizedthe protocol to generate a response rate of 72% using lymphodepletion prior to AdaptiveCell Therapy.It cannot be certain that the TIL subsets preferentially recovered from the tumor biopsycorresponded to those that mediated complete elimination of tumor in this patient.Recently, a patient that went down to NIH and did the ACT therapy had a response only wherethe cells came from (lungs). The other tumors continued to progress.Are the TILs tumor specific based on where the cells were obtained during biopsy? Does thismean the other tumors mutated or are they missing some receptor or MHC I or II at the tumorsurface? The property of the T-CELL RECEPTOR which enables it to react with some antigens and not others. The specificity is derived from the structure of the receptors variable region which has the ability to recognize certain antigens in conjunction with the MAJOR HISTOCOMPATIBILITY COMPLEX molecule. 1
  2. 2. Adoptive Cell Transfer.. 57 days after transfer. CD8+ T-cell (CTLs) at the MaximumPropagationA tumor lesion excised from patient 9 before nonmyeloablating chemotherapy("pretreatment") exhibited scant CD8+ cells (left), strong stromal cell staining but weakstaining of tumor cells with antibody to MHC class I (center), and sporadic cell stainingwith an antibody to MHC class II (probably tumor macrophages) but minimal staining oftumor cells (right). In contrast, a sample resected 57 days after cell transfer ("posttreatment") exhibited a dense, diffuse CD8+ infiltrate and ubiquitous expression of bothMHC class I and class II molecules in tumor cells.Source: Cancer Regression and Autoimmunity in Patients After ClonalRepopulation with Antitumor Lymphocytes Originally published in Science Express on 19 September 2002 Science 25 October 2002: Vol. 298. no. 5594, pp. 850 - 854 DOI: 10.1126/science.1076514 2
  3. 3. Patients undergoing Anti-CTLA-4 Blockadge. Week7 = Day 49 maximum ALC.. CD8+T-cell (CTLs)Source: Dr. Jedd Wolchok 3
  4. 4. What I am trying to show is the growth curves for the various T-cells subsets with datafrom in vivo to back up the above graphic. With that in mind, we now have a betterunderstanding on the growth patterns of these cells. By applying dosing schedules to theclinical protocols of combinatorial therapy, we can optimize the clinical outcome. 4