Inclusion Criteria:
1. Participant must be 18 years of age or older at the time of signing the informed consent.
2. Participant has a histologically confirmed diagnosis of advanced/metastatic melanoma or relapsed refractory metastatic non-small cell lung cancer (NSCLC).
3. Cohort and indication specific criteria as follows:
1. Phase 1 and Phase 2 Cohort 1 (enrollment complete):
- Participants with unresectable or metastatic melanoma must have experienced documented radiographic disease progression after systemic therapy containing a programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) blocking antibody.
- Participants with melanoma must not exceed 2 prior lines of systemic therapy. Neoadjuvant/Adjuvant treatment will not be considered a prior line of systemic therapy unless the participant progressed during or within the 12 weeks after the last dose of the adjuvant PD-1/PD-L1 blocking antibody.
2. Phase 1 and Phase 2 Cohort 2 (recruiting):
- Participants with non-small cell lung cancer should have relapsed or are refractory to approved systemic therapies (approved ICI-based regimen for all appropriate participants and/or an approved targeted therapy for known molecular abnormalities if applicable to their disease).
- Participants who received PD-1/PD-L1 inhibitor-based therapy in the adjuvant or neoadjuvant setting and whose disease relapsed or progressed to metastatic disease within 6 months of their last systemic PD-1/PD-L1 treatment are eligible without requiring additional treatment in the metastatic setting.
- Participants who experienced disease progression following a prior cytotoxic chemotherapy-based regimen may have received no more than one additional chemotherapy-containing regimen. However, participants must not have had disease progression while receiving this second-chemotherapy containing regimen.
3. Phase 2 Cohort 3 (recruiting):
- Participants with unresectable or metastatic melanoma must have experienced documented radiographic disease progression after systemic therapy containing a programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) blocking antibody.
- Participants with melanoma must not exceed 2 prior lines of systemic therapy. Neoadjuvant/Adjuvant treatment will not be considered a prior line of systemic therapy unless the participant progressed during or within the 12 weeks after the last dose of the (neo)adjuvant PD-1/PD-L1 blocking antibody.
- Participants with targetable BRAF mutations are not required to have received prior BRAF inhibitors. Participants must not have disease progression on a BRAF/MEK inhibitor that was given as the most recent line of therapy.
4. Phase 2 Cohort 4 (recruiting):
- Participants with frontline unresectable or metastatic melanoma.
- Participants may have received up to 2 doses of system therapy containing a programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) blocking antibody-based treatment of unresectable metastatic melanoma (but must not have known clinical progression prior to tumor procurement.) Neoadjuvant/Adjuvant treatment will not be considered a prior line of systemic therapy; however, participants whose disease progressed within 12 weeks after the last dose of the PD-1/PD-L1 blocking antibody given as (neo)adjuvant treatment (primary ICI resistant) are not eligible.
4. Participant is assessed as having at least one lesion (or aggregate lesions) suitable for OBX-115 generation.
5. After tumor tissue procurement, the participant will have at least one remaining measurable lesion, as defined by RECIST v1.1.
6. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and an estimated life expectancy of greater than 6 months.
7. Participant has recovered from all prior anticancer treatment-related AEs to at least Grade 1 (per Common Terminology Criteria for Adverse Events \[CTCAE\]).
8. Participants must have completed post-operative recovery from any prior surgical procedures with wound healing and resolution of all surgical complications prior to planned tumor procurement surgery.
9. Both male and female (women of childbearing potential) participants agree to the follow protocol specified contraceptive and/or abstinence requirements.
10. Participant has protocol specified hematologic parameters for absolute neutrophil count (ANC) and platelet count.
11. Participant has adequate cardiac, liver, lung, and kidney organ function as specified in the protocol.
Exclusion Criteria:
1. Participant has melanoma of uveal origin or its other genetic equivalents (e.g. GNA11 and GNAQ).
2. Participant has a history of brain metastases or leptomeningeal disease. Participants may be considered for enrollment if they have 4 or fewer brain metastatic lesions that are that have been treated, if clinically indicated. Asymptomatic brain metastases that are equivocal or too small to warrant treatment may not be counted towards the above set limits upon discussion and agreement from the Medical Monitor.
3. Participant has an active medical illness(es) that, in the opinion of the Investigator, would pose increased risks for study participation.
4. Participants with non-small cell lung cancer with refractory and clinically significant pleural effusions.
5. Participant has any form of primary or acquired immunodeficiency.
6. Participant has a history of hypersensitivity to any component of the study intervention.
7. Participant had another primary malignancy within the previous 3 years (with protocol specified exceptions).
8. Participant has a history of allogeneic organ transplant, allogeneic cell therapy, or genetically engineered cell therapy. Prior engineered TIL cell therapy is allowed.
9. Participant requires systemic steroid therapy of greater than10 mg/day of prednisone or equivalent.
10. Participant received a live or attenuated vaccination within 28 days prior to the start of lymphodepletion (LD).
11. Participant has evidence of positive infectious disease screening and/or any active uncontrolled viral, bacterial, or fungal disease requiring ongoing systemic treatment or identified during screening.