Dendritic Cell Therapy, Cryosurgery, and Pembrolizumab in Treating Patients With Non-Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. Evaluate the optimal dose schedule, safety and tolerability as measured by the incidence
of significant toxicity of combination therapy with anti-PD-1 monoclonal antibody,
cryoablation, and intra-tumor injection of autologous dendritic cell into the cryoablated
tumor. (Phase I) II. Test the efficacy (overall response rate) of combination therapy with
anti-PD-1 monoclonal antibody, cryoablation, and intra-tumor injection of autologous
dendritic cell vaccine. (Phase II)

SECONDARY OBJECTIVES:

I. Evaluate the feasibility of this combination immunotherapy. (Phase I) II. Evaluate patient
quality of life. (Phase I) III. Evaluate the partial response (PR) and complete response (CR)
rate of this combination immunotherapy. (Phase II) IV. Evaluate the progression free
survival, treatment free survival, duration of response, disease-free rate at 2 years, and
overall survival of this combination immunotherapy. (Phase II) V. Evaluate the safety of this
combination immunotherapy. (Phase II)

TERTIARY OBJECTIVES:

I. Assess the effect of combination immunotherapy on patients' immune status and anti-tumor
immune response.

II. Assess the potential association between PD-1/PD-L1/PD-L2 expression in tumor and blood
with clinical efficacy.

III. Assess the potential association between tumor antigen mutations and antigen-specific
immune response with clinical efficacy.

IV. Evaluate patient quality of life.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive pembrolizumab intravenously (IV) on day 1. Treatment repeats every 21 days
for up to 18 courses in the absence of disease progression or unacceptable toxicity. Patients
also receive dendritic cell therapy intratumorally (IT) on days 2, 8, and 15 of courses 2 and
3, and day 2 of courses 4 and 5. Patients undergo cryosurgery on day 2 of course 2 and
receive pneumococcal 13-valent conjugate vaccine by injection on day 2 of courses 2-5.
Treatment repeats every 21 days for up to 5 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 months during the
second year post-treatment, and then every 6 months for up to 2 years.

Inclusion Criteria:

- Histological confirmation of biopsy-proven non-Hodgkin lymphoma, excluding chronic
lymphocytic leukemia, primary central nervous system (CNS) lymphoma and Burkitt's
lymphoma; Note: small lymphocytic lymphoma (SLL) is allowed

- Patients with indolent non-Hodgkin lymphoma (NHL) must have had >= 1 regimen of
rituximab-containing regimen; Note: this includes follicular lymphoma (FL), marginal
lymphoma and mucosa-associated lymphoid tissue (MALT)

- Patient with aggressive NHL must have received prior therapy - at a minimum:

- Anti-CD20 monoclonal antibody unless tumor is CD20 negative and

- An anthracycline containing regimen

- Transformed FL must have had therapy for FL and be refractory to chemotherapy for
DLBCL

- Chemotherapy refractory disease in aggressive NHL is defined as

- Stable disease of =< 12 months or progressive disease as best response to most
recent chemotherapy containing regimen

- Disease progression or recurrence =< 12 months of prior autologous stem cell
transplantation (SCT)

- Patients with aggressive NHL must have failed autologous hematopoietic stem cell
transplantation (HSCT), or are ineligible or not consenting to autologous HSCT

- Patient must have at least 3 measurable lesions that are >= 1.5 cm in one dimension;
one of the lesions must be >= 2.0 cm and is amenable to image-guided cryoablation and
multiple vaccine injections as determined by interventional radiology and principal
investigator (PI) (including tumors that can be safely accessed using imaging guidance
and treated with minimal risk to adjacent structures)

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2

- Absolute neutrophil count (ANC) >= 1000/mm3

- Absolute lymphocyte count >= 500/mm3

- Platelet count >= 75,000/mm3

- Hemoglobin >= 8.0 g/dL

- Total bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert's disease

- Aspartate transaminase (AST/serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine transaminase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN

- Creatinine =< 1.5 x ULN or calculated creatinine clearance >= 60 mL/min for subject
with creatinine ˃ 1.5 x institutional ULN

- Negative serum pregnancy test for women of childbearing potential =< 7 days prior to
registration; Note: a second pregnancy test may be required =< 72 hours prior to
receiving the first dose of study medication

- Negative human immunodeficiency virus (HIV), hepatitis B and C, and tuberculosis (TB)
test

- Provide written informed consent

- Willing to return to the enrolling institution for follow-up (during active treatment
and active monitoring phase of the study)

- Ability to complete questionnaire(s) by themselves or with assistance

- Willing to provide tissue and blood samples for research purposes

- Willing to use adequate contraception while on the study and until 120 days after the
last dose of study drug

Exclusion Criteria:

- Any of the following:

- Pregnant women

- Nursing women

- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens

- Serious non-malignant disease such as active infection, symptomatic congestive heart
failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
situations or other conditions which in the opinion of the investigator would
compromise protocol objectives

- Currently receiving or have received any other investigational agent considered as a
treatment for the primary neoplasm =< 28 days or within 4 half-lives (whichever is
shorter) of the agent prior to registration

- History of other primary malignancy requiring systemic treatment within 6 months of
protocol enrollment; patients must not be receiving chemotherapy or immunotherapy for
another cancer; patients must not have another active malignancy requiring active
treatment with the following acceptable EXCEPTIONS:

- Basal cell carcinoma, squamous cell carcinoma, or melanoma of the skin that has
undergone or will undergo potentially curative therapy

- In situ cervical cancer that has undergone or will undergo potentially curative
therapy

- Prior allogeneic bone marrow or peripheral blood stem cell transplantation

- Prior autologous bone marrow or peripheral blood stem cell transplantation =< 100 days
prior to registration or if recovery from the transplant is inadequate

- Major surgery other than diagnostic surgery =< 4 weeks prior to registration

- Prior chemotherapy or radiation therapy =< 2 weeks prior to registration or who has
not recovered (i.e. to =< grade 1 or baseline) from an adverse event due to the
previously administered therapy

- History of hypersensitivity and anaphylactoid reactions to pneumococcal vaccine or any
component of the formulation, including diphtheria toxoid

- Active autoimmune disease such as Crohn's disease, rheumatoid arthritis, Sjogrens'
disease, systemic lupus erythematosis, or similar conditions requiring systemic
treatment within the past 3 months or a documented history of clinically severe
autoimmune disease/syndrome difficult to control in the past

- EXCEPTIONS:

- Vitiligo or resolved childhood asthma/atopy

- Intermittent use of bronchodilators or local steroid injections

- Hypothyroidism stable on hormone replacement,

- Diabetes stable with current management

- History of positive Coombs test but no evidence of hemolysis

- Psoriasis not requiring systemic treatment

- Conditions not expected to recur in the absence of an external trigger

- Coagulopathy, including the use of Coumadin or heparin anticoagulants that cannot be
discontinued for the cryoablation procedure; NOTE: heparin for line patency without
detectable lab abnormalities for coagulation will be allowed

- Corticosteroid use =< 2 weeks prior to registration; NOTE: patients must be off
corticosteroids for at least 2 weeks prior to registration; this includes oral, IV,
subcutaneous, or inhaled route of administration; patients on chronic corticosteroid
for adrenal insufficiency or other reasons may enroll if they receive less than 10
mg/day of prednisone (or equivalent)

- Active CNS malignancy

- Evidence of interstitial lung disease or active, non-infectious pneumonitis

- Received a live vaccine =< 30 days prior to registration

- New York Heart Association classification III or IV cardiovascular disease or recent
myocardial infarction or unstable angina pectoris or cardiac arrhythmia =< 30 days
prior to registration