PSMA Therapy and Immunotherapy in Kidney Cancer

Inclusion Criteria: 1. Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of clear cell RCC will be enrolled in this study. 2. Participants must have progressed on treatment with an anti-PD-1/L1 ICI administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria: 1. Treatment with at least 6 weeks of an approved anti-PD-1/L1 ICI. 2. More than one prior line of anti-PD-1/L1 ICI is allowed. 3. The immediate prior line of therapy is not mandated to be with anti-PD-1/L1 ICI. 4. Postoperative or adjuvant systemic therapy can be counted as a prior ICI therapy as long as recurrence is detected within 6 months of completion of treatment, in which case it will be counted as a prior therapy for metastatic disease. 3. Metastatic or locally advanced inoperable clear cell RCC. 4. Participants who have AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. 5. Evidence of positive PSMA avid lesions as per (F-18)-DCFPyL PSMA PET scan at screening. Positive lesions on PSMA-PET are defined as those with maximum standardized uptake value (SUVmax) values greater than liver as assessed by the local site investigator radiologist. 6. At least 70% of all the following lesions must PSMA-PET positive: 1. Lymph nodes that measure ≥ 25 mm in short axis on anatomic imaging. 2. Bone metastasis with soft tissue component ≥ 10 mm in short axis. 3. Solid organ metastasis ≥ 10 mm in short axis. 7. A maximum of 4 prior lines of systemic therapy is allowed, including more than one line of ICI regimens. 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 with a life expectancy ≥ 6 months 9. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial. 10. Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. 11. Female subjects of childbearing potential must be non-pregnant, non-lactating, and have a urine or serum pregnancy test within 24 hours prior to administration of each PNT-2002 dose. 12. Females of childbearing potential who are sexually active with a non-sterilized male partner agree to use effective methods of contraception from screening, throughout the study treatment and agree to continue using such precautions for 4 months after the final dose of study drug. 13. Non-sterilized males who are sexually active with a female of childbearing potential must agree to use effective methods of contraception from Day 1 throughout the study treatment and for 6 months after the final dose of study drug. 14. Have adequate organ function. Blood Specimens must be collected within 7 days prior to the start of study intervention. Exclusion Criteria: 1. Renal cell carcinoma with non-clear cell histology. 2. Prior exposure to radioligand therapy or radioisotope therapy. 3. Treatment with RCC standard of care anti-cancer therapy within 14 days prior to initiation of study treatment 4. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration. 5. PSMA targeted imaging within 2 weeks prior to screening. 6. Has received prior radiotherapy within 2 weeks of start of study intervention or radiation-related toxicities requiring corticosteroids. Note: Two weeks or fewer of palliative radiotherapy for non-central nervous system diseases permitted. The last radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention. 7. Must have recovered from any grade 3 or higher reversible toxicity to prior anti cancer therapy treatments. 8. Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed. 9. Has a diagnosis of immunodeficiency (e.g. patients who are known to be serologically positive for human immunodeficiency virus (HIV) or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. 10. Known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. Participants with low-risk early-stage prostate cancer (T1-T2a, Gleason score ≤6, and prostate-specific antigen (PSA) \<10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease are not excluded. 11. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention. 12. Has severe hypersensitivity (≥Grade 3) to pembrolizumab or (F-18)-DCFPyL (Pylarify) and/or any of their components. 13. Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid) 14. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. 15. Has an active infection requiring systemic therapy 16. Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable (HBV) DNA and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection. Note: Hepatitis B and C screening tests are not required unless: Known history of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection As mandated by local health authority 17. Has not adequately recovered from major surgery or has ongoing surgical complications. 18. Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator. 19. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 20. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment. 21. Has had an allogenic tissue/solid organ transplant. 22. Known history of HIV infection. HIV testing is not required unless mandated by local health authority.