Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Malignancies

Background: Blood cancers (such as leukemias) can be hard to treat, especially if they have mutations in the TP53 or RAS genes. These mutations can cause the cancer cells to create substances called neoepitopes. Researchers want to test a method of treating blood cancers by altering a person s T cells (a type of immune cell) to target neoepitopes. Objective: To test the use of neoepitope-specific T cells in people with blood cancers Eligibility: People aged 18 to 75 years with any of 9 blood cancers. Design: Participants will have a bone marrow biopsy: A sample of soft tissue will be removed from inside a pelvic bone. This is needed to confirm their diagnosis and the TP53 and RAS mutations in their cancer cells. They will also have a skin biopsy to look for these mutations in other tissue. Participants will undergo apheresis: Blood will be taken from their body through a vein. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different vein. The T cells will be grown to become neoepitope-specific T cells. Participants receive drugs for 3 days to prepare their body for the treatment. The modified T cells will be given through a tube inserted into a vein. Participants will need to remain in the clinic at least 7 days after treatment. Participants will have 8 follow-up visits in the first year after treatment. They will have 6 more visits over the next 4 years. Long-term follow-up will go on for 10 more years.

* INCLUSION CRITERIA: Malignancy diagnosis requirements: -Eligible diagnoses include AML (acute myeloid leukemia), MDS (myelodysplastic syndrome), CMML(chronic myelomonocytic leukemia), CML (chronic myeloid leukemia), and T-ALL (T-acute lymphoblastic leukemia/lymphoma) meeting standard diagnostic criteria as described in the 5th edition World Health Organization Classification of Hematologic Tumors and/or the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias. Multiple myeloma participants meeting International Working Group diagnostic criteria are eligible. These diagnostic criteria can be met at any time during the course of the participant s malignancy. Atypical CML is not an eligible diagnosis. NOTE: Pathology reports are acceptable to confirm eligibility. Malignancy mutation and HLA requirements: * Detection of at least one of the neoepitope-forming TP53 or RAS mutations that are listed in Table 3 in on the TruSight Oncology (TSO) 500 sequencing panel (NSR device) performed in the NCI Laboratory of Pathology is required. RAS mutations can be in NRAS, KRAS or HRAS as these oncogenes have the same amino acid sequence at the location of the targeted neoepitopes. A variant allele frequency (VAF) of at least 5% is required for a mutation to be eligible. This criterion can be met at any time within 60 days prior to apheresis regardless of treatment history during this 60-day period. DNA for sequencing comes from bone marrow. * Presence of the correct HLA type needed to present one of the targeted neoepitopes as shown in Table 3. HLA typing data from any time-point prior to apheresis can be used to meet this requirement. Table 3: Eligibility requirements for the targeted mutation and HLA type Targeted mutation - TP53 R175H; HLA Type - A\*02:01 Targeted mutation - TP53 Y220C; HLA Type - A\*02:01 Targeted mutation - TP53 R248W; HLA Type - A\*68:01 Targeted mutation - Ras G12V; HLA Type - A\*11:01 Targeted mutation - Ras G12D; HLA Type - A\*11:01 Targeted mutation - Ras G12D; HLA Type - C\*08:02 Targeted mutation - Ras G12V; HLA Type - C\*01:02 Malignancy burden requirements: * For AML and MDS, bone marrow myeloblast percentage must be \>=5% of nucleated cells in either bone marrow aspirate or biopsy. Myeloblasts can be defined by immunohistochemistry or by cytochemistry stains including but not limited to myeloperoxidase. * For T-ALL, bone marrow T-cell blast percentage must be \>=5% of nucleated cells in either bone marrow aspirate or biopsy. T cells can be defined by cytochemistry or immunohistochemistry or flow cytometry. * For multiple myeloma, plasma cells having a phenotype consistent with multiple myeloma must be detected at any frequency by multiparameter bone marrow flow cytometry or total plasma cells must be at least 6% on bone marrow core biopsy or bone marrow aspirate. * For CMML, bone marrow blast (including monocytic blast equivalent) percentage must be \>=6% of bone marrow nucleated cells by cytochemistry or immunohistochemistry of bone marrow aspirate or biopsy. * For CML measurable leukemia is defined as molecular detection of BCR-ABL1 at a ratio of \>1.0% to ABL1 or another housekeeping gene on The International Scale (IS) in either blood or bone marrow. Malignancy prior treatment and risk category criteria \- Participants with AML, MDS, CML, CMML, and T-ALL who have not had prior allogeneic hematopoietic stem cell transplantation (alloHSCT) must be unwilling or unable to undergo alloHSCT. NOTE: Unable to undergo alloHSCT could be due to lack of access to transplantation or not meeting transplant eligibility criteria at one or more transplant centers where the participant was evaluated by a transplant physician. * Participants with primary, secondary, or treatment-related AML that did not go into remission after induction therapy are eligible regardless of history of alloHSCT. * Myelodysplastic syndrome (MDS) * Participants with MDS must have had high or very high risk MDS as determined by IPSS-R or IPSS-M (https://mds-risk-model.com) at any time point. * Participants with MDS must have received previous treatment with at least one of the following: a hypomethylating agent, cytotoxic chemotherapy, or alloHSCT. Participants with primary or treatment-related MDS are eligible. * Participants with MDS/AML with mutated TP53 are eligible. * Participants with CMML must have had a CMML-specific prognostic scoring system-Molecular (CPSS-Mol) score of \>=2 (Intermediate-2 or High risk groups) at any time-point and must have received at least one line of previous systemic treatment, which could have been alloHSCT. * Chronic myeloid leukemia (CML) * Participants with chronic phase CML and a history of inadequate response to or intolerance of 3 or more tyrosine kinase inhibitors (TKIs) are eligible. * In addition, participants who have received at least one of bosutinib, dasatinib, or nilotinib in addition to either ponatinib or asciminib are eligible. Participants in accelerated phase or blast crisis are eligible if they have received at least one TKI. * Participants who have received a prior HSCT are eligible provided they have also received at least 2 TKIs and meet other eligibility criteria. * Participants with T-ALL must have T-ALL that did not go into CR with induction therapy or that relapsed. * Participants with relapsed AML who are unable to undergo alloHSCT and meet other eligibility requirements are eligible. * Multiple Myeloma * Participants with multiple myeloma must have received at least 3 different prior systemic treatment regimens for multiple myeloma. Participants must have prior exposure to an imid such as lenalidomide, a proteosome inhibitor, and a BCMA-targeting CAR T-cell therapy, such as monoclonal antibody, or bispecific antibody. * Multiple myeloma participants with a history of alloHSCT are eligible * Participants with multiple myeloma must also have measurable multiple myeloma defined by at least one of the criteria below: * Serum M-protein greater or equal to 1.0 g/dL. * Urine M-protein greater or equal to 200 mg/24 h. * Serum free light chain (FLC) assay: involved FLC level greater or equal to 10mg/dL (100 mg/L) provided serum FLC ratio is abnormal. * A biopsy-proven plasmacytoma at least 2.0 cm in largest dimension. * Bone marrow core biopsy with 30% or more plasma cells. Other inclusion criteria * Blast cells \=45,000/mcL without transfusion support in the 7 days prior to the blood count check * Absolute neutrophil count: \>=850/mcL without exogenous growth factor administration within the 10 days prior to the blood count check * Total bilirubin: \38 degrees within the past 24 hours without a known non-infectious source or participants requiring intravenous antibiotics when intravenous antibiotics have been administered for less than 72 hours. * Acti...