Autologous T-cells Genetically Engineered to Express Receptors Reactive Against KRAS Mutations in Conjunction With a Vaccine Directed Against These Antigens in Participants With Metastatic Cancer

Phase

Condition

Urologic Cancer

Pelvic Cancer

Colon Cancer; Rectal Cancer

Treatment

Fludarabine

GRT-C903/GRT-R904

KRAS TCR-Transduced PBL

Clinical Study ID

NCT06253520

10001662

001662-C

Ages 18-72
All Genders

Study Summary

Background:

Many cancer cells produce substances called antigens that are unique to each cancer. These antigens stimulate the body s immune responses. One approach to treating these cancers is to take disease-fighting white blood cells from a person, change those cells so they will target the specific proteins (called antigens) from the cancer cells, and return them to that person s blood. The use of the white blood cells in this manner is one form of gene therapy. A vaccine may help these modified white cells work better.

Objective:

To test a cancer treatment that uses a person s own modified white blood cells along with a vaccine that targets a specific protein.

Eligibility:

Adults aged 18 to 72 years with certain solid tumors that have spread after treatment.

Design:

Participants will undergo leukapheresis: Blood is removed from the body through a tube attached to a needle inserted into a vein. The blood passes through a machine that separates out the white blood cells. The remaining blood is returned to the body through a second needle.

Participants will stay in the hospital for 3 or 4 weeks. They will take chemotherapy drugs for 1 week to prepare for the treatment. Then their modified white cells will be infused through a needle in the arm. They will take other drugs to prevent infections after the infusion.

The vaccine is injected into a muscle; participants will receive their first dose of the vaccine on the same day as their cell infusion.

Participants will have follow-up visits 4, 8, and 12 weeks after the cell infusions. They will receive 2 or 3 additional doses of the boost vaccine during these visits.

Follow-up will continue for 5 years, but participants will need to stay in touch with the gene therapy team for 15 years.

...

Eligibility Criteria

Inclusion

INCLUSION CRITERIA:
Participants with an appropriate HLA match for available Surgery Branch KRAS TCRswith evaluable metastatic solid cancer (e.g., gastrointestinal, genitourinary,breast, ovarian, non-small cell lung cancer (NSCLC) and other solid cancers) withknown KRAS G12V or G12D mutation.
Confirmation of diagnosis of cancer by the NCI Laboratory of Pathology.
Refractory to standard systemic therapy. Specifically:
Participants with metastatic colorectal cancer must have received oxaliplatinand/or irinotecan.
Participants with breast and ovarian cancer must have received at least twosystemic treatments.
Participants with NSCLC must have received at least one platinum-basedchemotherapy regimen and at least one FDA-approved targeted treatment (whenappropriate).
Participants with other solid tumors must have received at least one prior lineof systemic treatment or have declined standard treatment.
Participants with three (3) or fewer brain metastases that are < 1 cm indiameter each and asymptomatic are eligible. Lesions that have been treatedwith stereotactic radiosurgery must be clinically stable for one month aftertreatment for the participant to be eligible. Participants with surgicallyresected brain metastases are eligible.
Age >= 18 years and <= 72 years.
Clinical performance status of ECOG 0 or 1.
Individuals of child-bearing potential (IOCBP) must agree to use highly effectivecontraception (hormonal, intrauterine device [IUD, abstinence, surgicalsterilization starting at the time of study entry, for the duration of studytherapy, and 12 months after the last dose of combined chemotherapy

Participants who can father a child must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) for the duration of the study treatment and for 4 months after the last dose of combined chemotherapy. We also will recommend participants that can father children with partners of childbearing potential to ask their partners to be on highly effective birth control (hormonal, intrauterine device (IUD), surgical sterilization).

NOTE: IOCBP is defined as any person who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal.

NOTE: Certain malignancies may secrete hormones that produce false positive pregnancy tests. Serial blood testing (e.g. HCG measurements) and/ or ultrasound may be performed for clarification.

Participants must have serology results as follows:
Seronegative for HIV antibody.
Seronegative for hepatitis B antigen, and seronegative for hepatitis Cantibody. If hepatitis C antibody test is positive, then participant must betested for the presence of antigen by RT-PCR and be HCV RNA negative.
Adequate organ and marrow function as defined below:

--Hematology:

ANC > 1000/mm^3 without growth factor support
WBC >= 2500/mm^3
Platelet count (Bullet) 80,000/mm3
Hemoglobin > 8.0 g/dL. Subjects may be transfused to reach this cut-off.
Chemistry:
Serum ALT/AST <= 5.0 x ULN
Serum creatinine <= 1.6 mg/dL
Total bilirubin <= 2.0 mg/dL, except in participants with Gilbert s Syndrome, whomust have a total bilirubin < 3.0 mg/dL.
Participants must have completed any prior systemic therapy at the time ofenrollment.

NOTE: Participants may have undergone minor surgical procedures or limited field radiotherapy within the four weeks prior to enrollment, as long as related major organ toxicities have recovered to grade 1 or less.

For participants with NSCLC or lung metastases, more than two weeks must haveelapsed since any prior palliation for major bronchial occlusion or bleeding at thetime the patient receives the preparative regimen, and patient s toxicities musthave recovered to a grade 1 or less.
Ability of subject to understand and the willingness to sign a written informedconsent document.
Willing to sign a durable power of attorney.
Participants must be co-enrolled on protocol 03-C-0277.

Exclusion

EXCLUSION CRITERIA:

Participants who are pregnant or nursing because of the potentially dangerouseffects of the treatment on the fetus or infant.
Any form of secondary immunosuppression.
Active systemic infections requiring anti-infective treatment, coagulationdisorders, or any other active or uncompensated major medical illnesses.
For participants with NSCLC or lung metastases, any major bronchial occlusion orbleeding not amenable to palliation.
Any form of primary immunodeficiency (such as Severe Combined ImmunodeficiencyDisease and AIDS).
History of major organ autoimmune disease.
Concurrent opportunistic infections (The experimental treatment being evaluated inthis protocol depends on an intact immune system. Participants who have decreasedimmune-competence may be less responsive to the experimental treatment and moresusceptible to its toxicities.)
History of severe immediate hypersensitivity reaction to cyclophosphamide,fludarabine, aldesleukin or vaccines.
Clinically significant participant history which in the judgment of the PrincipalInvestigator (PI) would compromise the participants ability to tolerate high-dosealdesleukin.
History of coronary revascularization or ischemic symptoms.
For select participants with a clinical history prompting cardiac evaluation: lastknown LVEF <= 45%.
For select participants with a clinical history prompting pulmonary evaluation:known FEV1 <= 50% predicted.

Study Design

Fludarabine

May 16, 2024

June 15, 2033

Study Description

Background:

The majority of cancer deposits from patients with melanoma or solid epithelial cancers contain tumor infiltrating lymphocytes (TIL) that can recognize unique mutated neoantigens expressed by the cancer.
Administration of autologous TIL to patients with metastatic melanoma can mediate complete durable regression in up to 24% of patients with metastatic melanoma. The administration of TIL from patients with solid epithelial cancers mediate far fewer clinical responses probably because the frequency of these anti-tumor T cells in solid epithelial cancers is very low (often less than 0.1%).
We have developed approaches to adoptive cell transfer (ACT) therapy that involves isolating T-cell receptors (TCR) that recognize mutated cancer neoantigen. These TCRs are transduced into autologous peripheral lymphocytes to express these TCRs with high efficiency. These neoantigen TCR gene-modified cells can recognize and destroy the autologous cancer in vitro.
In a single patient with chemo-refractory metastatic colon cancer, we identified a rare population of neoantigen reactive TIL targeting the KRAS G12D hotspot mutation and administration of these TIL mediated a near-complete regression of all metastatic disease now lasting over 5 years. The administration of cells genetically modified to express anti KRAS G12D receptors obtained from this patient have now been used to mediate regression of metastatic pancreatic cancer in a patient containing a G12D mutation. Using targeted screening and in vitro sensitization of PBL and TIL, we have now identified a library of TCRs capable of recognizing the KRAS G12D or KRAS G12V shared mutations restricted by a variety of Class I or Class II MHC restriction elements.
In murine experiments utilizing T-cell receptors against mutated antigens, we have shown that cells bearing these receptors are far more effective in mediating anti-tumor responses against established tumors when cell administration is combined with a vaccine targeting the same antigen targeted by the T cells.
Gritstone bio has developed a prime boost adenoviral/mRNA vaccine targeting KRAS G12D and G12V shared mutations.
The clinical protocol described here will treat participants with chemorefractory solid cancers that express G12D or G12V KRAS mutations using the adoptive transfer of autologous lymphocytes transduced with genes encoding TCRs that recognize these mutations in conjunction with the administration of an anti-KRAS vaccine.

Objectives:

-Primary objective:

--Determine the safety and efficacy of administering autologous T cells transduced to express receptors targeting KRAS G12D or G12V mutations in conjunction with an anti-KRAS vaccine to participants with metastatic solid cancers that contain KRAS G12D or G12V mutations.