Ability of a Dendritic Cell Vaccine to Immunize Melanoma or Epithelial Cancer Patients Against Defined Mutated Neoantigens Expressed by the Autologous Cancer

Background:

- Therapeutic vaccination against cancer has proven very challenging with little clinical
benefit.

- Vaccines against non-viral tumors have mainly targeted differentiation antigens, cancer
testis antigens, and overexpressed antigens. However negative selection in the thymus
against these normal nonmutated antigens severely limits the ability to generate high
avidity anti-cancer T cells. Such depletion can impair their antitumor activity and
limit tumor elimination.

- The National Cancer Institute Surgery Branch (NCI SB ) has developed a pipeline for the
identification of immunogenic T cell epitopes derived from neoantigens.

- In recent studies, we identified the neoantigens recognized by TIL that mediated
regression in patients with metastatic cancer. Using whole exome sequencing of a
resected metastatic nodule followed by high throughput immunologic screening, we were
able to demonstrate that tumor regressions were associated with the recognition by the
administered TIL of unique somatic mutations that occurred in the cancer.

- We, therefore, aim to use this pipeline to identify immunogenic neoantigens from
epithelial cancer patients and to use these defined epitopes for a personalized
therapeutic dendritic cell (DC) vaccine.

Objectives:

-Primary objectives:

--To determine the clinical response rate in patients with metastatic melanoma or epithelial
cancer who receive this DC vaccine

Eligibility:

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

- ECOG 0 - 2

- Evaluable metastatic melanoma or epithelial cancer refractory to standard treatment

- Metastatic melanoma or epithelial cancer lesion(s) that is resectable for TIL or in
selected cases, available PBMC.

Design:

- Patients with metastatic melanoma or epithelial cancer will undergo surgical resection
of tumor followed by exome and RNA sequencing to identify expressed mutations (CONDUCTED
UNDER THE nci sb COMPANION PROTOCOL 03-c-0277).

- Patients will undergo apheresis and DC will be cryopreserved for vaccine preparation.

- Immunogenic neoantigens will be identified from TIL and PBMC by high throughput
immunologic screening using long peptides and tandem minigenes covering all mutated
epitopes.

- Patient will be vaccinated with autologous mature dendritic cells loaded with long
peptides and minimal epitopes from defined neoantigens or highly expressed mutations in
tumor suppressor or driver genes.

- DC will be administered intravenously and subcutaneously for four cycles at biweekly
intervals.

- Blood samples will be taken every two weeks, and patients will be monitored for the
quantity and quality of circulating neoantigen-specific T cells.

- INCLUSION CRITERIA:

- Metastatic melanoma or epithelial cancer with at least one lesion that is resectable
or in selected cases, available PBMCs

- Measurable and evaluable metastatic disease per RECIST 1.1 criteria

- Confirmation of the diagnosis of metastatic cancer by the Laboratory of Pathology of
NCI.

- All patients must be refractory to approved standard systemic therapy.

- Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and
asymptomatic are eligible. Lesions that have been treated with stereotactic
radiosurgery must be clinically stable for one month after treatment for the patient
to be eligible. Patients with surgically resected brain metastases are eligible.

- Greater than or equal to 18 years of age and less than or equal to 70 years of age.

- Clinical performance status of ECOG 0, 1, 2

- Patients of both genders must be willing to practice birth control from the time of
enrollment on this study and for up to four months after treatment.

- Serology:

- Seronegative for HIV antibody. (The experimental treatment being evaluated in
this protocol depends on an intact immune system. Patients who are HIV
seropositive can have decreased immune-competence and thus are less responsive to
the experimental treatment and more susceptible to its toxicities.)

- Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody.
If hepatitis C antibody test is positive, then the patient must be tested for the
presence of antigen by RT-PCR and be HCV RNA negative.

- Hematology

- Absolute neutrophil count greater than 1000/mm^3 without the support of
filgrastim

- WBC greater than or equal to 3000/mm^3

- Platelet count greater than or equal to 100,000/mm^3

- Hemoglobin > 8.0 g/dl. Subjects may be transfused to reach this cut-off.

- CD4 count > 200/uL

- Chemistry:

- Serum ALT/AST less than 5.0 x ULN

- Serum Creatinine less than or equal to 1.6 mg/dl

- Total bilirubin less than or equal to 2.0 mg/dl, except in patients with
Gilbert's Syndrome, who must have a total bilirubin less than or equal to 3.0
mg/dl.

- More than four weeks must have elapsed since any prior systemic therapy at the time
the patient receives the vaccine, and patients toxicities must have recovered to a
grade 1 or less (except for toxicities such as alopecia or vitiligo).

Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as
long as all toxicities have recovered to grade 1 or less.

- Ability of subject to understand and the willingness to sign a written informed
consent document.

- Subjects must be co-enrolled On protocol 03-C-0277.

EXCLUSION CRITERIA:

- Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the treatment on the fetus or infant.

- Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
Disease).

- Concurrent opportunistic infections (The experimental treatment being evaluated in
this protocol depends on an intact immune system. Patients who have decreased immune
competence may be less responsive to the experimental treatment and more susceptible
to its toxicities).

- Active systemic infections (requiring anti-infective treatment), coagulation disorders
or any other active or uncompensated major medical illnesses.

- Patients who are receiving any other investigational agents.