Background: Myeloid cells are a type of immune cell found in most tumors. Interleukin 12 (IL-12) is a protein that helps the immune system kill tumor cells. Researchers want to know if myeloid cells that have been genetically engineered to produce IL-12 (IL-12 GEMys) can activate the immune system to attack cancer cells in solid tumors. Objective: To test IL-12 GEMys in people with cancer. Eligibility People aged 18 years and older with cancer that returned or failed to respond to treatment. Design: Participants will be screened. They will have a physical exam with blood tests. They will have tests of their heart and lung function. They will have imaging scans of their tumors. A sample of tumor tissue may be taken. Participants will have daily injections for few days to prepare them to undergo leukapheresis: Blood will be taken from the body through a needle inserted into a vein. The blood will pass through a machine that separates out stem cells. The remaining blood will be returned to the body through a different needle. The collected stem cells will be modified in a lab to create IL-12 GEMys. Participants will check in to the hospital. They will receive drugs for 5 days to prepare their body for the treatment. Then they will have their own IL-12 GEMys infused through a needle inserted into a vein. They will stay in the hospital until they are well enough to go home. This may be 7 to 14 days or longer. Some participants may receive a second treatment with IL-12 GEMys within 2 years after the first. Participants will have follow-up visits for about 5 years. These will include imaging scans and blood tests.
Background: * Myeloid cells are found in virtually all tumors, and they can play diverse roles in the tumor microenvironment including phagocytosing dying tumor cells, presenting antigen, suppressing anti-tumor immunity, and limiting natural killer (NK) and dendritic cell (DC) differentiation and function. * Hematopoietic stem and progenitor cells (HSPCs) and myeloid cells can be genetically modified to express cytokines, such as the anti-tumor cytokine interleukin (IL)-12, which can be delivered locally by recruited myeloid cells in tumor and metastatic tissues. * IL-12 is an important immunostimulatory cytokine. It can promote multiple effectors in adaptive immunity including enhancing major histocompatibility complex (MHC) class I expression, activation of NK cells, and DC maturation, and is essential for the T-helper 1 (Th1) response in T cells. * A human lentiviral vector encoding single chain IL-12 gene and a truncated human epidermal growth factor receptor (EGFRt) have been developed. This lentivirus encodes a single chain bioactive IL-12 obtained by fusing the p35 and p40 subunits with a flexible (Gly4Ser)3 linker and can be used to transduce apheresed CD34+ HSPCs. * Genetically engineered myeloid (GEMy) cells that secrete IL-12 (IL-12 GEMys) show efficacy in metastatic murine models including sarcomas, pancreatic carcinoma, and breast carcinoma. When IL-12 GEMys are combined with cyclophosphamide and fludarabine conditioning, long-term cure of large primary and metastatic solid tumors in mice occurs. These results suggest that IL-12 GEMys may have anti-tumor metastatic activity in humans. Objectives: * Part A (escalation): To determine the recommended phase 2 dose (RP2D) of IL-12 GEMys in participants with relapsed or refractory solid tumors following a cyclophosphamide and fludarabine conditioning regimen or without conditioning regimen. * Part B (expansion): To assess whether IL-12 or IFN(gamma) levels, or both, increase in tumors post-treatment at the RP2D compared to levels seen in pre-treatment tumors. Eligibility: * Participants \>= 18 years with relapsed or refractory solid tumor malignancies except primary tumors of the central nervous system (CNS) for whom standard measures do not exist or are no longer effective and have measurable or evaluable disease. * There are no limits on prior therapy. * Participants must be willing to undergo mandatory pre- and post-treatment tumor biopsies (Part B only). Design: * This is a Phase I, dose escalation/de-escalation trial design. * Participants will undergo leukapheresis to obtain CD34+ cells that will then be genetically modified to express an IL-12 lentiviral vector with EGFRt. Differentiation to myeloid cells will occur after transduction. * Depending on Dose Level, participants may or may not receive a lymphocyte-depleting therapy consisting of cyclophosphamide and fludarabine with the intent of enhancing the activity of the infused IL-12 GEMys. * There will be an expansion cohort at the RP2D. * On Day 0, participants will receive an infusion of IL-12 GEMys. * Participants will be evaluated sequentially for toxicity, antitumor effects, and other biological correlatives. * If an adequate number of additional cells are available for an additional dose, the participant may be offered the option of retreatment.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
95
Cell therapy generated from autologous CD34+ cells. Administered on Day 0 as an IV infusion not to exceed 20ml/kg or 40ml/kg depending on DMSO levels.
Lymphodepletive chemotherapy administered as 30 mg/kg IV infusion over 1 hour daily on days -6 and -5.
Lymphodeleptive chemotherapy administered as 25 mg/m\^2 IV infusion over 30 minutes on days -6 through -2.
Administered as IV infusion at 500 mg/m\^2, if needed.
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Part A (Escalation): Determine the recommended phase 2 dose (RP2D) of IL-12
Maximum dosage of GEMys IL-12 with which no more than 1 participant experience dose limiting toxicity as assessed by grade of adverse event
Time frame: 0-28 Days
Part B (Expansion): Assess whether IL-12 or IFNy levels, or both increase in tumors post treatment at the RP2D
Increased IL-12 and/or IFNy levels and IL-12 production as measured by ELISA, using a paired t-test or Wilcoxon signed rank test
Time frame: 1 week
Determine the feasibility of manufacturing IL-12 GEMys that express a truncated epidermal growth factor receptor (EGFRt) meeting release criteria
Number of participants at each dose level for whom the target number of cells at that dose level can be manufactured and assessed prior to infusion
Time frame: Time of cell infusion
Determine the safety of IL-12 GEMys
Safety data will be analyzed per standard methods and interpreted descriptively for each dose level. Ongoing analysis of toxicity using CTCAE and RCL collected from the blood
Time frame: 0-12 months
Assess the antitumor activity of IL-12 GEMys
Overall response rate (ORR) (PR + CR) per RECIST 1.1
Time frame: 0-5 years
Assess the re-treatment utility of IL-12 GEMys
Assessment of clinical response per RECIST
Time frame: 0-5 years
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