Clinical Trial Finder

Inclusion Criteria:

• - Participant must be HLA-A2+.

Retesting is not required for patients who have previous documented positivity.

• - Have IO-refractory melanoma with primary PD-1/PD-L1resistance.

Note: Any lines of prior therapies are allowed, but the last line needs to include an anti PD-1 or anti PD-L1 agent. The prior treatments may include any standard and/or experimental therapies.

• - Have >= 1 tumor site amenable to core needle biopsy that is not the site of disease used to measure antitumor response.

• - Have measurable disease based on RECIST 1.1 criteria present.

• - Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

• - Platelets >= 75,000/microliter.

• - Hemoglobin >= 9 g/deciliter.

• - Absolute neutrophil count (ANC) >= 1500/microliter.

• - Creatinine < 1.5 x institutional upper limit of normal (ULN) OR creatinine clearance >= 50 mL/min by Cockcroft-Gault formula for subjects with creatinine levels >= 1.5 x ULN.

• - Total bilirubin not greater than 1.5 x institutional ULN, except for patients with known Gilbert's Syndrome, who are eligible to no more than 2 x institutional ULN.

• - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) no greater than 3 x institutional ULN OR, no greater than 5 x ULN for subjects with liver metastases.

• - Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry.

Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

• - Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure.

• - Candidate for continuation/resumption of anti-PD-1/PD-L1 blockade (in parallel to DC vaccine and CKM)

  Exclusion Criteria:

  - Is currently being treated with systemic immunosuppressive agents, including steroids: Subjects will be ineligible until 3 weeks after removal from immunosuppressive treatments, except when they are administered as replacement therapy for endocrine dysfunction (and receive no more than 10 mg prednisone or equivalent: inhaled steroids are allowed) - Has had prior anti-cancer therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., no more than grade 1 or at baseline) from adverse events due to a previously administered agent, except for neuropathy (no more than grade 2) or alopecia or vitiligo (any grade) - Has a known additional malignancy that is progressing or requires active treatment.

• - Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.

Treated brain metastases are allowed, if stable for more than 4 weeks (and receive no more than 10 mg prednisone or equivalent: inhaled steroids are allowed).

• - Has a history of cardiac event(s) (acute coronary syndrome, myocardial infarction, or ischemia (within 3 months of signing consent) or, subject has a New York Heart Association classification of III or IV.

• - Has an active infection requiring systemic therapy.

• - Has known active hepatitis B or hepatitis C infection.

• - Has known immunosuppressive disease (e.g. human immunodeficiency virus [HIV], acquired immunodeficiency syndrome [AIDS] or other immune depressing disease).

Testing is not mandatory.

• - Has known serious hypersensitivity reactions to pegylated (peg)-interferon alpha-2b or interferon alpha-2b.

• - Prior allergic reaction or hypersensitivity to sulfonamides, celecoxib, or nonsteroidal anti-inflammatory drugs (NSAIDs) - Has received a blood transfusion in the two weeks prior to leukapheresis.

• - Women of child bearing potential who are pregnant or nursing.

• - Unwilling or unable to follow protocol requirements.

• - Any condition which in the Investigator's opinion deems the participant an unsuitable candidate or unacceptable risk to receive study drug regimen.

- Patients who showed initial response to PD-1/PD-L1 blockade and developed secondary resistance

PRIMARY OBJECTIVE:

• I. To evaluate the objective response rate to treatment with an autologous alpha-type-1 polarized dendritic cells (alphaDC1)/TBVA cell-based treatment (alpha-type-1-polarized dendritic cells loaded with tumor blood vessel-targeting antigenic peptides) plus cytokine modulating (CKM) regimen (rintatolimod, recombinant interferon alpha-2 [IFN-alpha2b] and, celecoxib) in human leukocyte antigen (HLA)-A2+ subjects with primary PD-1 resistant immuno-oncology (IO)-refractory melanoma (who will continue the original PD-1/PD-L1 regimen for 12 weeks).

SECONDARY OBJECTIVES:

• I. To evaluate the immune-related objective response rate (objective response rate [ORR]; per immune-related Response Evaluation Criteria in Solid Tumors [iRECIST];) in the above patient population treated with autologous alphaDC1/TBVA cell-based treatment plus cytokine CKM regimen followed by continued treatment with PD-1/PD-LI blockade (+/- CTLA4 blockade or LAG3 blockade).

• II. Evaluate rate of durable responses (> 6 months) on the combination treatment in the above patient population treated with autologous alphaDC1/TBVA cell-based treatment plus cytokine CKM regimen followed by continued treatment with PD-1/PD-L1 blockade (+/- CTLA4 blockade or LAG3 blockade).

EXPLORATORY OBJECTIVES:

• I. Examine whether the combination of peptide-loaded autologous alphaDC1 cell-based treatment and tumor-selective chemokine modulation (CKM: IFN-a2b, rintatolimod, and celecoxib) improves the overall survival (OS) and immune-related progression-free survival (iPFS) in HLA-A2+ subjects PD-1/PD-L1-refractory melanoma compared to the historical control of the best supportive care.

• II. Identify the intratumoral and systemic immune correlates of the response to treatment.

OUTLINE: Patients receive recombinant interferon alpha-2 intravenously (IV) over 30 minutes, rintatolimod IV over 2.5 hours, and celecoxib orally (PO) twice daily (BID) on days 1-3. Beginning cycle 2, patients also receive alpha-type-1 polarized dendritic cells intradermally (ID) on day 1. Treatment repeats every 3 weeks up to 4 cycles in the absence of disease progression or unacceptable toxicity. At 12 weeks, patients with progressive disease may switch to ipilimumab with or without a PD-1/PD-L1 inhibitor and patients with a complete response (CR), partial response (PR), or stable disease (SD) may switch to a PD-1/PD-L1 inhibitor or best alternative care. After completion of study treatment, patients are followed up every 3 months for up to 2 years.

Arms

Experimental: Treatment (IFNA2, rintatolimod, celecoxib, alphaDC1 cell based treatment)

Patients receive recombinant interferon alpha-2 IV over 30 minutes, rintatolimod IV over 2.5 hours, and celecoxib PO BID on days 1-3. Beginning cycle 2, patients also receive alpha-type-1 polarized dendritic cells ID on day 1. Treatment repeats every 3 weeks up to 4 cycles in the absence of disease progression or unacceptable toxicity. At 12 weeks, patients with progressive disease may switch to ipilimumab with or without a PD-1/PD-L1 inhibitor and patients with a complete response CR, PR, or stable disease SD may switch to a PD-1/PD-L1 inhibitor or best alternative care.

Interventions

Biological: - Alpha-type-1 Polarized Dendritic Cells

Given ID

Drug: - Celecoxib

Given PO

Drug: - PD-1 Ligand Inhibitor

Given IV

Drug: - PD1 Inhibitor

Given IV

Biological: - Recombinant Interferon Alfa-2b

Given IV

Drug: - Rintatolimod

Given IV