Study of KYV-101 Anti-CD19 CAR T Therapy in Adult Dermatomyositis

Inclusion Criteria:

1. Diagnosis of probable or definite (>55%) IIM and subgroup classification asdermatomyositis according to the 2017 EULAR/ACR classification criteria foridiopathic inflammatory myopathies.

2. Age > 25 years and < 72 years at time of signing informed consent Refractorydisease: subject with previous failure (or intolerance) to glucocorticoids and atleast two non-glucocorticoid immunosuppressive therapies (including mycophenolatemofetil or mycophenolic acid, cyclophosphamide, azathioprine, methotrexate,calcineurin inhibitors, tofacitinib or other JAK inhibitors, rituximab, or IVIG)administered for at least 12 weeks within 24 months prior to screening.

.Moderate-to-severe dermatomyositis as per EITHER: muscle weakness, defined as Manual Muscle Testing (MMT-8) score <142/150; or cutaneous disease as per Cutaneous Dermatomyositis Assessment and Severity Index-activity subscore (CDASI-a)>=19.

PLUS at least 2 other abnormal IMACS Core Set Measures (CSMs) from the following:

• Patient global VAS≥2 cm.

• Physician's global VAS ≥2 cm.

• Global extramuscular activity score ≥2 cm.

• Elevation of at least one of the muscle enzymes (CK, AST, ALT, aldolase, LDH) >1.5times upper limit of normal.

• HAQ-DI≥0.25.

2.For patients enrolling on the MMT-8 criterion, muscle disease must be active, asdeemed by one of the following:

• Creatine kinase, aldolase, LDH, AST, or ALT (if deemed due to muscle inflammation byinvestigator) ≥2×ULN.

• MRI evidence of active myositis within last 3 months.

• EMG evidence of active myositis within last 3 months.

Other inclusion criteria: Subject must sign a written ICF prior to any screening procedures.

1. Subject must be ≥25 and ≦72 years of age.

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

3. Adequate organ function as per table below. Haematology Haemoglobin: ≥10.0 g/dl (without prior red blood cell transfusion within 7 days before the laboratory test)aPlatelets: ≥100,000/ μL (without transfusion support within 7 days before thelaboratory test). Absolute Lymphocyte Count (ALC):≥700/μL Absolute Neutrophil Count (ANC) 1,500/μL (prior growth factor support is permitted but must be without support in the 7 daysprior to the laboratory test) Hepatic AST and ALT: ≤2.5×upper limit of normal (ULN)unless deemed by the investigator to be secondary to DM. Total bilirubin ≤1.5×ULN; except in subjects with congenital bilirubinaemia, such asGilbert syndrome (in which case direct bilirubin ≤1.5×ULN is required) RenalCreatinine clearance Calculated creatinine clearance ≥45 mL/min/1.73 m2 (measured byCockcroft-Gault equation) Pulmonary Grade≤1 dyspnoea Oxygen saturation measured bypulse oximetry ≥92% on room air a .For subjects who meet the inclusion criteria atscreening, transfusion of red blood cells is permitted after screening as needed tomaintain a haemoglobin level ≥8.0 g/dL.

4. Must be up to date on all recommended vaccinations, including against COVID-19/ SARSCoV-2, per Centers for Disease Control and Prevention or institutional guidelinesfor immune-compromised individuals.

5. Women of childbearing potential must have a negative pregnancy test at screeningusing a highly sensitive serum pregnancy test (β-human chorionic gonadotropin [β-hCG]). Women of childbearing potential are defined as a sexually mature woman whohas not undergone a hysterectomy or tubal ligation or who has not been naturallypostmenopausal for at least 24 consecutive months.

6. Female subjects of childbearing potential who have a fertile male sexual partnermust agree to use a highly effective method of contraception (failure rate of <1%per year when used consistently and correctly) from the time of signing the ICFuntil 1 year after the KYV-101 infusion. Examples of highly effective method ofcontraception include:

• Established use of hormonal methods of contraception associated with inhibitionof ovulation (eg, oral, inserted, injected, implanted, transdermal), providedthe subject or male subject's female partner plans to remain on the sametreatment throughout the entire study and has been using that hormonalcontraceptive for an adequate period of time to ensure effectiveness.

• Correctly placed copper containing- intrauterine device or intrauterinehormone-replacing system.

• Male sterilization with absence of sperm in the post-vasectomy ejaculate.

• Female sterilization (bilateral tubal ligation/bilateral salpingectomy orbilateral tubal occlusive procedure (provided that occlusion has beenconfirmed).

• Sexual abstinence, defined as completely and persistently refraining from allheterosexual intercourse (including during the entire period of risk associatedwith the study treatments) may obviate the need for contraception ONLY if thisis the preferred and usual lifestyle of the subject.

7. Male subjects, if not surgically sterilized, must agree to use highly effectivemethod of contraception and not donate sperm from the time of signing the ICF until 1 year after the KYV-101 infusion.

8. For females: a negative pregnancy test at screening and prior to lymphodepletionchemotherapy.

9. Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively,until at least 1 year after receiving a KYV-101 infusion.

EXCLUSION CRITERIA:

DM-related exclusion criteria

1. Evidence of any of the following:

• Severe muscle damage as per one of the following criteria:

1. Myositis Global Damage Index (MDI) ≥5.
2. Severe proximal muscle atrophy of upper or lower extremity on MRI.
3. Severe proximal muscle atrophy of upper or lower extremity on clinicalexamination.
4. Wheelchair-bound at home.
5. MMT-8 of ≤80.

• MDA5-positive rapidly progressing interstitial lung disease (subjects withstable ILD not requiring supplemental oxygen are eligible).

• Findings of muscular inflammation or myopathy other than the indication, suchas polymyositis (PM), immune mediated necrotizing myopathy (IMNM), inclusionbody myositis (IBM), cancer-associated myositis (myositis diagnosed within 2years of cancer), drug-induced myopathy, amyloid myopathy, muscular dystrophy,metabolic myopathies, or myositis in the context of significant overlap withanother systemic autoimmune rheumatologic disease (overlap myositis), exceptwith Sjogren's syndrome.

• Generalized, severe musculoskeletal or neuro-muscular conditions other than DMthat prevent a sufficient assessment of the patient by the investigator.

2. Subject with any of the following:

• Patients with ILD associated with any of the following oRequiring O2 therapyand/or FVC ≤45% of predicted or DLCO ≤40% of predicted at screening oEvidenceof PH as defined as estimated RVSP or ≥45 mmHg or right atrial or ventricularenlargement or dilatation, unless subsequent RHC shows no PH.

oPAH on right heart catheterization requiring PAH specific treatment.

•Current gangrene of a digit

Other exclusion criteria:

1. Prior treatment with cellular immunotherapy (eg, CAR T) or gene therapy productdirected at any target.

2. History of allogeneic or autologous stem cell transplant.

3. Systemic autoimmune disease, other than DM, requiring systemic immunosuppressivetherapies

4. Plan to receive live, attenuated vaccine after signing ICF (inactive vaccines, likethe flu vaccine, are allowed). Unable to washout or interrupt autoimmune diseasetherapy prior to apheresis as specified in Table .

5. Positive hepatitis B surface antigen (HBsAg) and hepatitis C serology confirmed bypolymerase chain reaction (PCR) (except hepatitis C cured with pharmacotherapy);subjects who are HBsAg negative and hepatitis B core antibody (HBc) positive with nodetectable DNA will be allowed into the study but will require regular monitoring ofhepatitis B virus (HBV) DNA.

6. Positive serology for human immunodeficiency virus (HIV).

7. Positive screening test for SARS-Cov-2.

8. Primary immunodeficiency.

9. History of splenectomy.

10. History of stroke, seizure, dementia, Parkinson's disease, coordination movementdisorder, cerebellar diseases, psychosis, paresis, aphasia, and any other neurologicdisorder investigator considers would increase the risk for the subject.

11. Impaired cardiac function or clinically significant cardiac disease including:

12. Unstable angina or myocardial infarction or coronary artery bypass graft (CABG)within 6 months prior to apheresis.

13. New York Heart Association (NYHA) stage III or IV congestive heart failure.

14. History of clinically significant cardiac arrhythmia (eg, ventriculartachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block.

15. History of severe nonischaemic cardiomyopathy.

16. Left ventricular ejection fraction (LVEF) <45% as assessed by echocardiogram (ECHO)

17. Previous or concurrent malignancy with the following exceptions:

18. Adequately treated basal cell or squamous cell carcinoma (adequate woundhealing is required prior to screening).

19. In situ carcinoma of the cervix or breast, treated curatively and withoutevidence of recurrence for at least 3 years prior to screening.

20. A primary malignancy which has been completely resected, or treated, and is incomplete remission for at least 5 years prior to screening.

21. Serious and/or uncontrolled medical condition that, in the investigator's judgment,would cause unacceptable safety risk, interfere with study procedures or results, orcompromise compliance with the protocol, such as:

22. Active, uncontrolled, viral, bacterial or systemic fungal infection (includinghuman T cell lymphotropic virus [HTLV], human polyomavirus 2 [JC virus], orsyphilis); or recent history of repeated infections.

23. Requirement of supplemental oxygen to maintain oxygen saturation.

24. Clinical evidence of dementia or altered mental status.

25. A thromboembolic event within 6 months prior to apheresis.

26. Ongoing toxicity from previous therapy that has not resolved to baseline levels orto Grade 1 or less, except for alopecia, fatigue, nausea, and constipation.

27. Major surgery within 4 weeks prior to apheresis or planned within 4 weeks afterKYV-101 administration. For surgery planned after 4 weeks post KYV-101administration, discuss with the sponsor.

28. Contraindications or life-threatening allergies, hypersensitivity, or intolerance toKYV-101 or its excipients, including dimethyl sulfoxide; or to CYC (or tofludarabine if relevant), or to tocilizumab.

29. Pregnant or breastfeeding; or plans to become pregnant or breastfeed, or father achild within 1 year after receiving the KYV-101 infusion.