A Phase 1/2 Study of KSQ-004EX, Autologous Tumor Infiltrating Lymphocytes Engineered to Inactivate Genes Encoding SOCS1 and Regnase-1, in Patients With Select Advanced Solid Tumors

Inclusion Criteria:

1. Diagnosed with one of the following tumor types:

2. Unresectable, incurable and/or metastatic histologically and/or cytologicallyconfirmed cutaneous, acral, or unknown primary melanoma (Stage IIIC or StageIV) that has progressed following at least 1 and no more than 3 lines of priortherapy in the advanced/metastatic setting, one of which includes treatmentwith anti-PD-1/PD-L1 inhibitor alone or in combination with anti-cytotoxic Tlymphocyte associated protein 4 (anti-CTLA-4) inhibitor or in combination withanti-LAG-3 antibody. Note: Up to 5 mucosal patients can be treated in the melanoma expansion cohort only.

3. Histologically and/or cytologically confirmed primary diagnosis of NSCLC whichhas progressed on at least 1 line and no more than 4 lines of prior therapy inthe advanced/metastatic setting, including platinum-based chemotherapy andcheckpoint inhibitor therapy (either given in combination or sequentially).

i. Participants with tumors that have known actionable molecular alteration such asepidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS-1,B-Raf proto-oncogene (BRAF), rearranged during transfection (RET), MET and KirstenRat Sarcoma Virus (KRAS) must have progressed on standard directed molecular therapyin addition to platinum-based chemotherapy. Note, the following do not count towards a line of prior therapy:

• Any therapy/regimen discontinued due to intolerance/tolerability issues

• Retreatment with the same class or previous class of treatment alone or incombination c. Locally advanced recurrent and/or metastatic histologicallyand/or cytologically confirmed HNSCC that has been previously treated with atleast 1 and no more than 4 lines of prior therapy in the advanced/metastaticsetting. i. Participants must have received a platinum-containing chemotherapy regimenfor the treatment of primary tumor in locally advanced, or metastatic setting d. Advanced, metastatic histologically and/or cytologically confirmedcolorectal adenocarcinoma that has progressed following at least 1 and no morethan 3 lines of prior therapy. Participants with dMMR/MSI-H or KRASG12C BRAFV600E mutation must have progressed on standard directed therapy. e. Locally advanced, recurrent, or metastatic histologically and/orcytologically confirmed pancreatic ductal adenocarcinoma (PDAC) that hasprogressed following at least 1 and no more than 3 lines of prior therapy inthe advanced/metastatic setting. f. Recurrent, metastatic, or persistent histologically and/or cytologicallyconfirmed squamous cell carcinoma (SCC), adenosquamous carcinoma, oradenocarcinoma of the cervix that is not amenable to curative treatment withsurgery and/or radiation therapy that has progressed following at least 1 andno more than 3 lines of prior therapy in the advanced/metastatic setting.

2. Resectable lesion for KSQ-004EX manufacturing (tumor ≥ 1.5 cm2 or at least 5 coreneedle biopsies)

3. At least one measurable lesion per RECIST v1.1 (Eisenhauer 2009) following tumorresection for KSQ-004EX manufacturing Note: Lesions in previously irradiated areasshould not be selected as a target lesion unless radiation treatment was ≥ 3 monthsprior, and there has been demonstrated disease progression in the lesion

4. Age ≥ 18 years of age

5. Life expectancy of ≥ 12 weeks

6. Recovered to ≤ Grade 1 or Baseline toxicity (except alopecia, neuropathy, andendocrinopathies from prior immunotherapy) from prior therapy (per the NationalCancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE])

7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

8. Adequate bone marrow function defined as:

9. Absolute neutrophil count (ANC) of ≥ 1 × 109/L

10. Platelet count of ≥ 100.0 × 109/L

11. Hemoglobin of ≥ 9.0 g/dL

12. Adequate renal function defined as calculated creatinine clearance (Cockcroft-Gault) ≥ 40 mL/min

13. Adequate hepatic function defined as:

14. Total bilirubin ≤ 2.0 × upper limit of normal (ULN) unless associated withGilbert's syndrome

15. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × ULN (or ≤ 5 × ULN in patients with liver metastases)

16. Washout period from prior anticancer therapy(ies) of a minimum duration (excludingbridging therapy per concomitant medication, see Section 6.11) is required prior tothe first study treatment (i.e., start of LDC therapy) as detailed below:

17. Targeted therapy: prior targeted therapy with an EGFR, ALK, receptor tyrosinekinase, or other-directed agent (eg, erlotinib, afatinib, osimertinib,crizotinib, ceritinib), is allowed provided the washout is a minimum of 7 daysor 5 half-lives, whichever is longer prior to start of therapy (LDC)

18. Monoclonal antibodies with a washout of at least 21 days or 5 half-lives orwhichever is longer

19. Chemotherapy: adjuvant, neoadjuvant or definitive chemotherapy/chemoradiationis allowed provided the washout is a minimum of 21 days or 5 half-lives,whichever is shorter

20. Radiation therapy: prior external beam radiation is allowed provided a minimumof 14 days have elapsed between the last dose of radiation and first studytreatment (LDC)

21. Surgery: previous surgical procedure(s) is permitted provided that woundhealing has occurred and at least 14 days have elapsed (for major operativeprocedures) prior to the first study treatment (LDC)

22. Female participants who are women of childbearing potential (WOCP), (defined asphysiologically and anatomically capable of becoming pregnant), confirmed of anegative pregnancy test and agreement to the use of a highly effective contraceptivemethod or at least 2 effective methods at the same time during study treatmentperiod and for up to 3 months after study treatment (KSQ-004EX infusion). Maleparticipants must be willing to use effective barrier contraception (ie, condoms)during the study treatment period and for up 3 months after study treatment (KSQ-004EX infusion)

a. This includes all female participants, between the onset of menses (as early as 8years of age) and 55 years unless the participant presents with an applicableexclusionary factor which may be one of the following: i. Postmenopausal (no mensesin greater than or equal to 12 consecutive months).

ii. History of hysterectomy or bilateral salpingo-oophorectomy. iii. Ovarian failure (follicle stimulating hormone and estradiol in menopausal range, who have receivedwhole pelvic radiation therapy).

iv. History of bilateral tubal ligation or another surgical sterilization procedure.

b. Approved methods of birth control are as follows: hormonal contraception (ie,birth control pills, injection, implant, transdermal patch, vaginal ring),intrauterine device (IUD), tubal Ligation or hysterectomy, subject/partnerpost-vasectomy, implantable or injectable contraceptives, and condoms plusspermicide. Not engaging in sexual activity for the total duration of the trial andthe drug washout period is an acceptable practice; however periodic abstinence, therhythm method, and the withdrawal method are not acceptable methods of birthcontrol. Should a woman become pregnant or suspect she is pregnant while she or herpartner is participating in this study, she should inform her treating physicianimmediately.

13. Ability to understand and the willingness to sign a written informed consentdocument

14. Signed and dated Institutional Review Board (IRB) approved informed consent form (ICF) before any protocol-directed Screening procedures are performed

Exclusion Criteria:

1. Prior organ allograft or prior cell therapy that included LDC or myeloablativechemotherapy regimen

2. Known hypersensitivity to any component of KSQ-004EX or excipient including dimethylsulfoxide, human serum albumin, LDC regimen (cyclophosphamide or fludarabine) orIL-2 (as applicable)

3. Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [eg, Grade ≥ 2 colitis or Crohn's disease], systemiclupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis withpolyangiitis], rheumatoid arthritis, etc.]). The following are exceptions to thiscriterion:

4. Participants with vitiligo or alopecia

5. Participants with hypothyroidism (eg, following Hashimoto syndrome) stable onhormone replacement

6. Any chronic skin condition that does not require systemic therapy

7. Participants with celiac disease controlled by diet alone

8. Hypersensitivity to antibiotics of the aminoglycoside group (eg, streptomycin,gentamicin) or penicillin

9. Active, uncontrolled concurrent infection requiring IV antibiotics present atScreening

10. Uveal and/or ocular melanoma

11. Large cell neuroendocrine NSCLC (defined as pathology with >10% neuroendocrinecomponents)

12. Symptomatic and/or untreated brain metastases (of any size or number) includingactive leptomeningeal or parenchymal metastases. Note: Participants with definitively treated brain metastases may be considered forenrollment if stable (defined as stable for 1-month post-central nervous systemdirected therapy) after discussion with the drug provider (KSQ)

13. Participants with ascites

14. Women who are pregnant or nursing

15. Seropositive for human immunodeficiency virus (HIV) 1 or 2 or acquiredimmunodeficiency syndrome, or active infection with hepatitis B virus (HBV) orhepatitis C virus (HCV) Note: Participants with positive HCV antibody may beeligible if HCV ribonucleic acid (RNA) is undetectable on a quantitative HCV RNAassay, following discussion with the drug provider (KSQ)

16. Any form of primary immunodeficiency (eg, Severe Combined Immunodeficiency Disease)

17. Any known clinically significant or concurrent acute liver disease, including viralhepatitis

18. Previous solid organ or hematopoietic cell transplant

19. Need for treatment with steroids at stable doses (> 10 mg/day prednisone orequivalent)

20. Topical, ophthalmic, or inhaled steroid medications are allowed

21. Systemic steroid (>10 mg/day) use is not allowed for 14 days prior toenrollment

22. Systemic steroids < 10 mg/day are permitted if for supplemental endocrine onlyNote: steroids can be administered for IV contrast allergy

23. Live or unattenuated vaccine < 28 days prior to first dose of LDC regimen

24. History of stroke, transient ischemic attack, unstable angina, or myocardialinfarction, within 3 months prior to first dose of study treatment

25. Symptomatic congestive heart failure according to New York Heart Association (NYHA)classification, Class III or IV (per NYHA Classification), unstable angina pectoris,clinically significant cardia arrhythmia, or left ventricular ejection fraction < 45%

26. Prolongation of QT/QTc interval (QTc interval > 480 msec) using the Frederica methodof QTc analysis

27. Unable to walk a distance of 80% predicted for age and sex or develop hypoxia (SPO2 < 90%) during a 6-minute walk test (this test can be performed in place of pulmonaryfunction test [PFT] for those unable to perform a reliable PFT due to complex upperairway anatomy)

28. For participants receiving IL-2 only: evidence of ischemia on cardiac stress test

29. > 80% stenosis based on carotid doppler ultrasound for patients with NSCLC and HNSCCwith > 35 pack year smoking history

30. Obstructive or restrictive pulmonary disease Note: Post-bronchodilator values:forced expiratory volume (FEV1)/forced vital capacity > 70% or FEV1 > 50% ofpredicted normal are required for study entry

31. Suspected pneumonitis or interstitial lung disease (confirmed by radiography orcomputed tomography [CT])

32. Treatment on another study with other investigational therapeutic interventionalstudy within 28 days to start of LDC regimen

33. Known additional malignancy that is active and/or progressive requiring treatment;exceptions including basal cell or squamous cell skin cancer, or other cancer forwhich the participants has been disease-free for at least 2 years

34. Psychiatric illness/social situation that would limit compliance with studyrequirements, as determined by the Investigator

35. Other severe, acute, or chronic medical condition or laboratory abnormality that mayincrease the risk associated with study participation or study drug administration,or that may interfere with the interpretation of the study results, and in thejudgement of the Investigator, would the participant inappropriate for the study