Background:

        -  The administration of autologous tumor-infiltrating lymphocytes (TIL) can mediate
           complete, durable regressions in 20-25% of participants with metastatic melanoma. Recent
           studies have shown that these TIL predominantly recognize unique mutated neoantigens
           expressed by the cancer not shared by other melanomas.

        -  Administration of bulk autologous TIL to participants with a variety of other solid
           cancers, including cancers of the gastrointestinal tract and genitourinary tract, have
           little if any therapeutic impact.

        -  Recent studies in the National Cancer Institute Surgery Branch, (NCI-SB), have shown
           that TIL from non-melanoma solid cancers can also contain T-cells reactive against
           non-shared unique mutated or oncoviral neoantigens expressed in the cancer. The
           frequency of these T-cells is very low (often < 0.1%) and it is thus difficult to
           isolate and grow mutation reactive T-cells to levels required for effective therapy.

        -  In a single patient with chemo-refractory metastatic cholangiocarcinoma we were able to
           grow a relatively pure population of neoantigen reactive TIL and administration of these
           cells mediated a near-complete regression of all metastatic disease now lasting 2.5
           years.

        -  We have developed approaches to identify these rare neoantigen reactive T-cells from
           common non-melanoma cancers, to isolate their T-cell receptors (TCR), and to genetically
           engineer autologous peripheral blood lymphocytes (PBL) to express these TCRs with high
           efficiency. The neoantigen TCR gene-modified cells can recognize and destroy the
           autologous cancer in vitro.

        -  In addition to reactivity to neoantigens derived from nonsynonymous mutations, T-cells
           can recognize human papilloma virus (HPV) epitopes in participants with HPV- induced
           cancers. The TCR from these reactive cells can be isolated and retrovirally-transduced
           into autologous PBL with high efficiency.

        -  With these techniques, we have isolated a number of TCRs selectively recognizing shared
           mutated oncogenes (e.g., KRAS, TP53) or shared oncoviral proteins (e.g. HPV) in the
           context of several major histocompatibility complexes (MHC-I and MHC-II).

        -  This clinical protocol will treat participants with refractory solid cancers using the
           adoptive transfer of autologous PBL transduced with genes encoding TCRs that recognize
           unique mutated or oncoviral neoantigens expressed by the cancer.

      Objectives:

      -Primary objective:

      --Determine the rate of objective response (using RECIST v1.1 criteria) of participants with
      solid cancers who receive pembrolizumab plus autologous PBL (Arm 2) that have been transduced
      with genes encoding T-cell receptors that recognize mutated or oncoviral neoantigens in the
      autologous cancer

      Eligibility:

      -Participants must be/have:

        -  Age greater than or equal to 18 years and less than or equal to 70 years

        -  Metastatic solid cancer with at least one lesion that can be measured, that falls into
           one of four cohorts: (1) gastrointestinal and genitourinary cancers; (2) breast,
           ovarian, and other solid cancers; (3) non-small cell lung cancer (NSCLC); and, (4)
           endocrine tumors including neuroendocrine tumors.

        -  Evaluable solid cancer that has recurred following standard chemotherapy or standard
           systemic therapy

        -  Normal basic laboratory values.

        -  No allergies or hypersensitivity to high-dose aldesleukin administration

        -  No concurrent major medical illnesses or any form of immunodeficiency.

      Design:

        -  Participants will have already undergone resection or biopsy to obtain tumor for
           generation of autologous TIL cultures. This will have been conducted under the NCI-SB
           cell harvest protocol 03-C-0277 (Cell Harvest and Preparation for Surgery Branch
           Adoptive Cell Therapy Protocols).

        -  Exomic sequencing, and often RNA-Seq will be performed to identify the mutations
           expressed in the patient s cancer. Multiple autologous TIL cultures will be grown and
           tested for reactivity against mutations from the autologous tumor using assays we have
           developed that involve the exposure of autologous antigen-presenting cells to long
           peptides containing the mutation or tandem mini-genes encoding the mutation.

        -  T-cell cultures with reactivity against mutations will be identified and the individual
           T- cell receptors that recognize the mutation will be synthesized and used to create a
           retrovirus for transduction of the TCR into the patient s autologous PBL.

        -  Participants that present with tumors expressing oncoviral neoantigens will be treated
           with autologous PBLs retrovirally transduced with TCR(s) targeting the oncoviral
           neoantigen.

        -  Participants that present with tumors expressing mutated shared oncogenes (e.g., KRAS,
           TP53) or oncoviral proteins (e.g., HPV) that also express the appropriate restriction
           element may be treated with autologous PBLs retrovirally transduced with TCR(s)
           previously isolated in the Surgery Branch targeting the shared mutated antigen. These
           participants will be administered a cell infusion product of TCRs targeting mutated
           shared oncogenes (e.g., KRAS, TP53) or oncoviral proteins (e.g., HPV). Their cell
           infusion product will not include PBL transduced with unique (i.e., non-shared) TCR(s).

        -  Participants will be enrolled into one of four cohorts: (1) metastatic gastrointestinal
           and genitourinary cancers; (2) metastatic breast, ovarian, and other solid cancers; (3)
           metastatic non-small cell lung cancer (NSCLC); and, (4) metastatic endocrine tumors
           including neuroendocrine tumors. Autologous PBL transduced with TCR(s) targeting
           neoantigens (mutated shared oncogenes e.g., TP53, KRAS, individual non-synonymous
           mutations , or oncoviral proteins) will then be expanded to large numbers using our
           standard rapid expansion protocol.

        -  Participants enrolled on Arm 1 and Arm 2 will receive a non-myeloablative,
           lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine
           followed by the infusion of autologous transduced PBL and high-dose aldesleukin. At the
           discretion of the Principal Investigator (PI), participants enrolled in Cohort 3 (NSCLC)
           may receive low-dose aldesleukin.

        -  Participants enrolled on Arm 2 will receive pembrolizumab prior to cell administration
           and three additional doses every three weeks following the cell infusion. Participants
           who have experienced major organ toxicity due to previous treatment with pembrolizumab
           (or equivalent PD-1/PD-L1 blockade) will be enrolled on Arm 1.

        -  Clinical and immunologic response will be evaluated about 4-6 weeks after cell infusion
           and periodically thereafter.

        -  It is anticipated that approximately one participant per month may enroll on the trial
           for each of the four histologic cohorts for Arm 2. There will be a limit of 15
           participants per cohort enrolled on Arm 1 (60 participants for Arm 1), and accrual of up
           to 4 x 50 = 200 total evaluable participants on Arm 2. It is expected that once full
           manufacturing capability is reached, the accrual may be completed in approximately 4-5
           years. In order to allow for a small number of inevaluable participants, the accrual
           ceiling will be set to 270.