- Adult patients with metastatic or unresectable Merkel cell polyomavirus
(MCPyV)-associated Merkel cell carcinoma (VP-MCC) that has progressed on or after
prior treatment with a PD-1 axis immune checkpoint inhibitor.
- Individuals that may be consented to undergo evaluation to determine potential
eligibility must have a history of metastatic or unresectable Merkel cell carcinoma
(as documented by medical record).
- Be capable of understanding and providing informed consent.
- TREATMENT PHASE:
- Participants must have metastatic or unresectable, histologically confirmed
virus-positive Merkel cell carcinoma. Confirmation of diagnosis must be or have been
performed by internal pathology review of initial or subsequent biopsy or other
pathologic material at Fred Hutchinson Cancer Research Center (FHCRC)/Seattle Cancer
Care Alliance (SCCA).
- Approximately 80% of MCCs are caused by Merkel cell polyomavirus T Antigens and the
treatment is expected to only be effective in this population. MCPyV positivity may be
established through immunohistochemistry of primary or metastatic MCC tumor lesion on
a clinical or research basis, positive MCPyV T antigen serology at any point during
the patients course, or presence of MCPyV deoxyribonucleic acid (DNA) or ribonucleic
(RNA) in the tumor lesion by research or clinical sequencing. Patients with negative T
antigen serology but MCPyV positive tumor by other methodologies will be considered
MCPyV positive, as the T antigen serology assays are highly specific (high true
positive rate) but incompletely sensitive for MCPyV status. T antigen expression may
be established at any point prior to singing the treatment consent.
- Participants must have measurable disease, defined as at least one target lesion that
can be measured in at least one dimension (longest diameter to be recorded) as ≥ 10
mm, unless lymph node in which case short axis must be >= 15 mm. For patients with
bone-only metastases, bony lesions can only be selected as a target lesion if they
have a measurable soft-tissue component. If a patient has only one measurable target
lesion, they must have a second MCC lesion (bone lesion, smaller lesion, etc.) that is
amenable to HLA upregulation (with single fraction radiation), in order to allow for
efficacy assessments; this second lesion does not need to be measurable. Baseline
imaging (for example computed tomography [CT] chest/abdomen/pelvis and imaging of the
affected extremity as appropriate), brain imaging (magnetic resonance imaging [MRI] or
CT scan) must be obtained within 45 days of prior to start of first planned
FH-MCVA2TCR infusion. Positron emission tomography (PET) CT or MRI can be substituted
for CTs as appropriate.
- Patients must have been previously treated with at least one dose of a PD-1 axis
inhibitor (e.g. PD-1 or PD-L1 inhibiting monoclonal antibody such as pembrolizumab,
nivolumab, avelumab, atezolizumab, durvalumab), developed progression of their MCC
tumor on or after treatment, and not developed grade III or higher toxicity. At least
four weeks must have passed between the administration of the first dose of PD-1 axis
inhibitor and determination of progression. If there is significant clinical concern
for pseudoprogression (i.e. progression developed rapidly after checkpoint inhibitor
therapy), biopsy must be performed to demonstrate true progression. Patients may have
received 1 or more prior systemic regimens for MCC. There is no upper limit on prior
regimens. Patients may have received prior anti-PD-1/anti-PD-L1 in the neoadjuvant or
- Participants must be HLA-A*02:01 in order for infused transgenic T cells to recognize
antigen-major MHC complexes.
- Life expectancy must be anticipated to be > 3 months at trial entry.
- Fewer than 0.5% of Merkel cell carcinomas occur in individuals aged 30 years or
younger, thus the protocol includes only adult patients.
- Capable of understanding and providing a written informed consent.
- If fertile, willingness to comply with reproductive requirements.
- Karnofsky performance status of >= 60%.
- Should there be no tumor tissue that is accessible for biopsy, patients will still be
considered for participation, at discretion of the investigator. Similarly, should an
investigator determine that a biopsy cannot be performed safely for clinical reasons
(e.g. active infection, no safe approach), biopsies may be cancelled or retimed at the
- At least 3 weeks must have passed since any: immunotherapy (for example, T-cell
infusions, immunomodulatory agents, interleukins, MCC vaccines, intravenous
immunoglobulin, expanded polyclonal tumor infiltrating lymphocyte [TIL] or
lymphokine-activated killer cell [LAK] therapy), natural killer (NK) therapy, small
molecule or chemotherapy cancer treatment, other investigational agents or other
systemic agents that target Merkel cell carcinoma. There is no washout period for
radiation, so long as radiated lesion is not the lesion targeted for irradiation or
Response Evaluation Criteria in Solid Tumors (RECIST) measurements on the protocol.
- Serum creatinine < 2.5 or estimated glomerular filtration rate (eGFR) > 30.
- Total bilirubin (tBili) < 3.0. Patients with suspected Gilbert syndrome may be
included if Tbili > 3 but no other evidence of hepatic dysfunction.
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5 x upper limit
of normal (ULN).
-=< grade 1 dyspnea.
- Oxygen saturation (SaO2) >= 92% on ambient air.
- If pulmonary function tests (PFTs) are performed based on the clinical judgment of the
treating physician, patients with forced expiratory volume in one second (FEV1) >= 50%
of predicted and diffusion capacity of the lung for carbon monoxide (DLCO) (corrected)
of >= 40% of predicted will be eligible.
- Patients 60 years of age or older are required to have left ventricular ejection
fraction (LVEF) evaluation performed within 1 year prior to study treatment. LVEF may
be established with echocardiogram or multigated acquisition (MUGA) scan, and must be
>= 35%. Cardiac evaluation for other patients is at the discretion of the treating
- Absolute neutrophil count (ANC) > 1000 cells/mm^3.
- Absolute lymphocyte count (ALC) > 200 cells/mm^3.
- Hematocrit (HCT) > 30%.
- Platelet count > 50K.
- Participants of childbearing potential must have a negative serum pregnancy test
within the 2 weeks preceding FH-MCVA2TCR infusion. Childbearing potential is defined
as women who have not been surgically sterilized and who are not post-menopausal (free
of menses for at least 1 year).
- Active autoimmune disease requiring immunosuppressive therapy is excluded unless
discussed with the principal investigator (PI).
- Kidney transplant will be considered on a case by case basis requiring discussion with
PI. If kidney transplant, patient must have dialysis access, dialysis plan, supportive
nephrologist, willingness to stop transplant immunosuppression, and express
understanding that rejection is likely. Dialysis or costs related to transplant kidney
will not be supported by the study. Participants having had any other solid organ
transplants will be excluded, as will those with a history of allogeneic stem cell
- Corticosteroid therapy at a dose equivalent of >10 mg prednisone per day.
- Concurrent use of other investigational agents or MCC directed therapies.
- Chronic lymphocytic leukemia (CLL) or other active hematologic malignancy.
- Human immunodeficiency virus (HIV) positive participants must be on highly active
antiretroviral therapy (HAART) with a CD4 count > 500 cells/mm^3 are considered
controlled, as are individuals with a history of hepatitis C who have successfully
completed antiviral therapy with an undetectable viral load, and those with hepatitis
B who have hepatitis well controlled on medication.
- Participants may not have uncontrolled or concurrent illness including, but not
limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
- Participants with small asymptomatic brain metastases (< 1 cm) or those with brain
metastases previously treated with surgery or radiotherapy will be considered for
inclusion at discretion of principal investigator, so long as other eligibility
criteria are met.
- Grade III or higher immune-mediated toxicity to any prior PD-1 axis blocking agent.
- Participants receiving treatment for prior immune-related adverse event (iRAE) are
excluded, with exception of hormone supplementation or corticosteroid therapy at
equivalent of up to 10 mg prednisone per day, unless otherwise approved by PI.
- Study participants must not have significant active underlying neurologic disease,
unless approved by PI. Mild neuropathy related to diabetes or prior chemotherapy is
- Other medical, social, or psychiatric factor that interferes with medical
appropriateness and/or ability to comply with study, as determined by PI.
- Any female patient who does not meet at least one of the following criteria will be
considered to have reproductive potential:
- Post-menopausal for at least 12 consecutive months (i.e., no menses), or
- Undergone a sterilization procedure (hysterectomy, salpingectomy, or bilateral
oophorectomy; tubal ligation is not considered a sterilization procedure)
- Pregnancy test for females of reproductive potential must be negative within 14 days
- Female patients with reproductive potential who are not sexually abstinent and male
patients who are sexually active with females of reproductive potential must agree to
use a suitable method of contraception for the duration of the study.