Personalized Cancer Vaccine (PCV) Strategy in Patients With Solid Tumors and Molecular Residual Disease

Inclusion criteria

Cohort #1:

• Age ≥ 18 years.
• ECOG performance status ≤ 2 (Karnofsky ≥ 60%).
• Histologically confirmed muscle-invasive bladder cancer (MIBC) or upper tract urothelial carcinoma (renal pelvis and/or ureter).
• Patients with carcinomas showing mixed histologies are required to have a dominant transitional cell pattern.
• Complete surgical resection of MIBC (R0) or upper tract urothelial carcinoma (renal pelvis and/or ureter). Tumor, nodes, metastases (TNM) classification (based on the American Joint Committee on Cancer (AJCC) Cancer Staging Manual 8th ed.) at pathological examination of surgical resection specimen as follows: pT2-4aN0M0 or pT0-4aN+M0.
• Patient must have fully recovered from surgical resection in the opinion of the treating MD.
• ctDNA positive result as identified by Signatera.
• Radiologic confirmation (by conventional imaging) of absence of residual disease and absence of metastasis.
• Adequate bone marrow and organ function as defined below:

• WBC ≥ 1.5 K/cumm
• Absolute neutrophil count ≥ 1.0 K/cumm
• Platelets ≥ 50 K/cumm
• Hemoglobin ≥ 8.0 g/dL
• Total bilirubin ≤ 1.5 x IULN
• AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
• Creatinine clearance > 30 mL/min by Cockcroft-Gault
• The effects of synthetic long peptide personalized cancer vaccines and Hiltonol on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 5 months after completion of study interventions. Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform her treating physician immediately.
• No concurrent investigational therapies outside of this protocol are allowed.
• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion criteria

Cohort #1:

• Receiving any other investigational agents, or planning to receive other investigational agents as part of neoadjuvant therapy. Patients who have received perioperative neoadjuvant chemotherapy and immunotherapy are allowed.
• Known allergy, or history of serious adverse reaction to vaccines such as anaphylaxis, hives, or respiratory difficulty.
• A psychiatric illness or social situations that would limit compliance with study requirements as determined by the investigator from the medical history, physical exam, and/or medical record.
• Prior or currently active autoimmune disease requiring management with immunosuppression. This includes inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic vasculitis, scleroderma, psoriasis, multiple sclerosis, hemolytic anemia, immune-mediated thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, or other rheumatologic disease or any other medical condition or use of medication (e.g., corticosteroids) which might make it difficult for the patient to complete the full course of treatments or to generate an immune response to vaccines. In the case of asthma or chronic obstructive pulmonary disease taking inhaled corticosteroids that does not require daily systemic corticosteroids is acceptable. Additionally, local acting steroids (topical, inhaled, or intraarticular) will be allowed. Patients on intermittent or short course steroids will be allow if the dose does not exceed 4 mg of dexamethasone (or equivalent) per day for > 7 consecutive days. Premedication for chemotherapy does not apply to this criterion and may be administered as per SOC practice. Any patients receiving steroids should be discussed with the PI to determine if eligible.
• Known HIV-positive status.
• History of positive test for Hepatitis B virus surface antigen (HBsAg) and/or positive Hepatitis C antibody result with detectable hepatitis C virus (HCV) ribonucleic acid (RNA) indicating acute or chronic infection
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia. For treatment enrollment the patient must have completed all prior cancer treatments > 28 days prior to vaccine administration with the exception of adjuvant SOC immunotherapy.
• Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial per discussion with the PI.
• Currently receiving any other investigational agents.
• Live vaccine administered within 30 days prior to enrollment.
• Immunodeficiency, systemic steroid therapy, or any other immunosuppressive therapy within 30 days of enrollment.
• Active autoimmune disease (excluding diabetes mellitus and/or vitiligo), solid organ or allogeneic bone marrow transplant, or other known contraindications to receiving immunotherapy.
• Severe hypersensitivity (grade ≥ 3) to checkpoint inhibitors and/or any of its excipients.
• Current pneumonitis, a history of (non-infectious) pneumonitis requiring steroids, or history of clinically significant interstitial lung disease.
• Active tuberculosis test within 3 months prior to treatment initiation.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum/urine pregnancy test within 14 days of prior to the first dose of vaccine.

Inclusion criteria

Cohort #2:

• Age ≥ 18 years.
• ECOG performance status ≤ 2 (Karnofsky ≥ 60%)
• Histologically confirmed gastroesophageal adenocarcinoma
• Stage II or III gastroesophageal adenocarcinoma (GEC).
• Complete surgical resection of GEC (R0). Full recovery from surgery and enrollment within 52 weeks following surgery with curative intent. Tumor, nodes, metastases (TNM) classification (based on the American Joint Committee on Cancer (AJCC) Cancer Staging Manual 8th ed.) at pathological examination of surgical resection specimen as follows:

• Esophageal and Esophagogastric junction adenocarcinoma T1 N1-3 M0 or T2-4 N0-2M0.
• Gastric adenocarcinoma T1-2 N1-3 M0 or T3-4 N0-3 M0.
• Patient must have fully recovered from surgical resection in the opinion of the treating MD.
• ctDNA positive result as identified by Signatera.
• Radiologic confirmation (by conventional imaging) of absence of residual disease and absence of metastasis.
• Adequate bone marrow and organ function as defined below:

• WBC ≥ 1.5 K/cumm
• Absolute neutrophil count ≥ 1.0 K/cumm
• Platelets ≥ 50 K/cumm
• Hemoglobin ≥ 8.0 g/dL
• Total bilirubin ≤ 1.5 x IULN
• AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
• Creatinine clearance > 30 mL/min by Cockcroft-Gault
• The effects of synthetic long peptide personalized cancer vaccines and Hiltonol and on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 5 months after completion of study interventions. Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform her treating physician immediately.
• No concurrent investigational therapies outside of this protocol are allowed.
• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion criteria

Cohort #2:

• Receiving any other investigational agents or planning to receive other investigational agents as part of neoadjuvant therapy. Patients who have received perioperative neoadjuvant chemotherapy and immunotherapy are allowed.
• Known allergy, or history of serious adverse reaction to vaccines such as anaphylaxis, hives, or respiratory difficulty.
• A psychiatric illness or social situations that would limit compliance with study requirements as determined by the investigator from the medical history, physical exam, and/or medical record.
• Prior or currently active autoimmune disease requiring management with immunosuppression. This includes inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic vasculitis, scleroderma, psoriasis, multiple sclerosis, hemolytic anemia, immune-mediated thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, or other rheumatologic disease or any other medical condition or use of medication (e.g., corticosteroids) which might make it difficult for the patient to complete the full course of treatments or to generate an immune response to vaccines. In the case of asthma or chronic obstructive pulmonary disease taking inhaled corticosteroids that does not require daily systemic corticosteroids is acceptable. Additionally, local acting steroids (topical, inhaled, or intraarticular) will be allowed. Patients on intermittent or short course steroids will be allow if the dose does not exceed 4 mg of dexamethasone (or equivalent) per day for > 7 consecutive days. Premedication for chemotherapy does not apply to this criterion and may be administered as per SOC practice. Any patients receiving steroids should be discussed with the PI to determine if eligible.
• Known HIV-positive status.
• History of positive test for Hepatitis B virus surface antigen (HBsAg) and/or positive Hepatitis C antibody result with detectable hepatitis C virus (HCV) ribonucleic acid (RNA) indicating acute or chronic infection.
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia. For treatment enrollment the patient must have completed all prior cancer treatments > 28 days prior to vaccine administration with the exception of adjuvant SOC immunotherapy.
• Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial per discussion with the PI.
• Currently receiving any other investigational agents.
• Live vaccine administered within 30 days prior to enrollment.
• Immunodeficiency, systemic steroid therapy, or any other immunosuppressive therapy within 30 days of enrollment.
• Active autoimmune disease (excluding diabetes mellitus and/or vitiligo), solid organ or allogeneic bone marrow transplant, or other known contraindications to receiving immunotherapy.
• Severe hypersensitivity (grade ≥ 3) to checkpoint inhibitors and/or any of its excipients.
• Current pneumonitis, a history of (non-infectious) pneumonitis requiring steroids, or history of clinically significant interstitial lung disease.
• Active tuberculosis test within 3 months prior to treatment initiation.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum/urine pregnancy test within 14 days prior to the first dose of the vaccine.

Inclusion criteria

Cohort #3:

• Age ≥ 18 years.
• ECOG performance status ≤ 1.
• Histologically or cytologically confirmed diagnosis of Melanoma. Stage IIB/C or IIIB-C (per AJCC 8th edition). Completed R0 resection within 36 months prior to enrollment and have fully recovered from surgery.
• Planning to receive or have received adjuvant immunotherapy for 1 year.
• Availability of a SignateraTM ctDNA report within 28 days prior to enrollment demonstrating ctDNA-positivity (MRD+). Note: Patients may be pre-screened prior to obtaining ctDNA results to facilitate assay design.
• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.
• Radiologic confirmation (by conventional imaging) of absence of residual disease and absence of metastasis.
• Adequate bone marrow and organ function as defined below:

• WBC ≥ 1.5 K/cumm
• Absolute neutrophil count ≥ 1.0 K/cumm
• Platelets ≥ 50 K/cumm
• Hemoglobin ≥ 8.0 g/dL
• Total bilirubin ≤ 1.5 x IULN
• AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
• Creatinine clearance > 30 mL/min by Cockcroft-Gault
• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion criteria

Cohort #3:

• Receiving any other investigational agents or planning to receive other investigational agents in the neoadjuvant or adjuvant setting.
• Known allergy, or history of serious adverse reaction to vaccines such as anaphylaxis, hives, or respiratory difficulty.
• A psychiatric illness or social situation that would limit compliance with study requirements as determined by the investigator from the medical history, physical exam, and/or medical record.
• Prior or currently active autoimmune disease requiring management with immunosuppression. This includes inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic vasculitis, scleroderma, psoriasis, multiple sclerosis, hemolytic anemia, immune-mediated thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, or other rheumatologic disease or any other medical condition or use of medication (e.g., corticosteroids) which might make it difficult for the patient to complete the full course of treatments or to generate an immune response to vaccines. In the case of asthma or chronic obstructive pulmonary disease, taking inhaled corticosteroids that do not require daily systemic corticosteroids is acceptable. Additionally, local acting steroids (topical, inhaled, or intraarticular) will be allowed. Patients on intermittent or short course steroids will be allowed if the dose does not exceed 4 mg of dexamethasone (or equivalent) per day for > 7 consecutive days. Systemic steroids must be discontinued at least 7 days prior to the first dose of SLP-01. Premedication for chemotherapy does not apply to this criterion and may be administered as per SOC practice. Any patients receiving steroids should be discussed with the PI to determine if they are eligible for this investigational treatment.
• History of allogeneic stem cell transplant of solid organ transplant.
• History of grade ≥3 immune-related adverse events with prior checkpoint inhibitors that, in the investigator's opinion, preclude further IO or vaccine therapy.
• Untreated or unstable CNS metastases.
• Known HIV-positive status.
• History of positive test for Hepatitis B virus surface antigen (HBsAg) and/or positive Hepatitis C antibody result with detectable hepatitis C virus (HCV) ribonucleic acid (RNA) indicating acute or chronic infection.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum/urine pregnancy test within 14 days prior to first dose of vaccine.

Inclusion criteria

Cohort #4:

• Age ≥ 18 years.
• ECOG performance status ≤ 1.
• Histological diagnosis of non-small cell lung carcinoma, stages II, IIIA or IIIB with complete R0 resection. Completed R0 resection within 9 months of surgery.
• Planned to receive or have received adjuvant immunotherapy for 1 year.
• Availability of a SignateraTM ctDNA report within 28 days prior to enrollment demonstrating ctDNA-positivity (MRD+). Note: Patients may be pre-screened prior to obtaining ctDNA results to facilitate assay design.
• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.
• Radiologic confirmation (by conventional imaging) of absence of residual disease and absence of metastasis.
• Adequate bone marrow and organ function as defined below:

• WBC ≥ 1.5 K/cumm
• Absolute neutrophil count ≥ 1.0 K/cumm
• Platelets ≥ 50 K/cumm
• Hemoglobin ≥ 8.0 g/dL
• Total bilirubin ≤ 1.5 x IULN
• AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
• Creatinine clearance > 30 mL/min by Cockcroft-Gault
• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion criteria

Cohort #4:

• Receiving any other investigational agents or planning to receive other investigational agents in the neoadjuvant or adjuvant setting.
• Known allergy, or history of serious adverse reaction to vaccines such as anaphylaxis, hives, or respiratory difficulty.
• A psychiatric illness or social situation that would limit compliance with study requirements as determined by the investigator from the medical history, physical exam, and/or medical record.
• Prior or currently active autoimmune disease requiring management with immunosuppression. This includes inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic vasculitis, scleroderma, psoriasis, multiple sclerosis, hemolytic anemia, immune-mediated thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, or other rheumatologic disease or any other medical condition or use of medication (e.g., corticosteroids) which might make it difficult for the patient to complete the full course of treatments or to generate an immune response to vaccines. In the case of asthma or chronic obstructive pulmonary disease, taking inhaled corticosteroids that do not require daily systemic corticosteroids is acceptable. Additionally, local acting steroids (topical, inhaled, or intraarticular) will be allowed. Patients on intermittent or short course steroids will be allowed if the dose does not exceed 4 mg of dexamethasone (or equivalent) per day for > 7 consecutive days. Systemic steroids must be discontinued at least 7 days prior to the first dose of SLP-01. Premedication for chemotherapy does not apply to this criterion and may be administered as per SOC practice. Any patients receiving steroids should be discussed with the PI to determine if they are eligible for this investigational treatment.
• Known EGFR activating mutations (exon 19 deletion or L858R) or ALK, RET, or ROS1 gene rearrangements in subjects for whom adjuvant targeted therapy is planned.
• History of allogeneic stem cell transplant or solid organ transplant.
• History of grade ≥3 immune-related adverse events with prior checkpoint inhibitors that, in the investigator's opinion, preclude further IO or vaccine therapy.
• Known HIV-positive status.
• History of positive test for Hepatitis B virus surface antigen (HBsAg) and/or positive Hepatitis C antibody result with detectable hepatitis C virus (HCV) ribonucleic acid (RNA) indicating acute or chronic infection.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum/urine pregnancy test within 14 days prior to the first dose of vaccine.