• Maximum tolerated dose (MTD) [ Time Frame: Up to 4 years ]
  MTD will be defined as the dose level that does not induce dose limiting toxicity in at least one-third of patients.
• Proportion of complete responses of combination therapy with pembrolizumab, cryoablation, and intra-tumor injection of autologous dendritic cells (DC) at maximum tolerated dose (MTD) dose [ Time Frame: Up to 4 years ]
  The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated.

• Maximum tolerated dose (MTD) defined as the dose level that does not induce dose limiting toxicity in at least one-third of patients [ Time Frame: Up to 4 years ]
• Proportion of complete responses of combination therapy with pembrolizumab, cryoablation, and intra-tumor injection of autologous DC at MTD dose [ Time Frame: Up to 4 years ]
  The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated.

• Complete response [ Time Frame: Up to 4 years ]
  The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated. The response rate will be calculated, in each individual cohort as supplementary.
• Progression free survival [ Time Frame: Up to 4 years ]
  The distribution of survival time will be estimated using the method of Kaplan-Meier.
• Treatment free survival [ Time Frame: From registration to next treatment or death due to any cause, assessed up to 4 years ]
  The distribution of treatment-free survival will be estimated using the method of Kaplan-Meier.
• Duration of response [ Time Frame: Up to 4 years ]
  The distribution of duration of complete response will be estimated using the method of Kaplan-Meier.
• Disease free survival rate [ Time Frame: At 2 years ]
• Overall survival [ Time Frame: From registration to death due to any cause, assessed up to 2 years ]
  The distribution of survival time will be estimated using the method of Kaplan-Meier.
• Incidence of adverse events [ Time Frame: Up to 4 years ]
  Will be assessed by Common Terminology Criteria for Adverse Events version 4.0. The maximum grade for each type of adverse event at each evaluation will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. Longitudinal analysis techniques will be utilized to determine the effect of time on treatment adverse events.
• Quality of life [ Time Frame: Up to 4 years ]
  Will be measured using the Functional Assessment of Cancer Therapy-lymphoma. The assessment will be scored according to the scoring algorithm. Changes from baseline will be calculated at each assessment time points. Mean change scores at each time point will be calculated to determine if quality of life is reduced over the course of treatment. Longitudinal techniques will be employed to describe changes over time.

• Complete response [ Time Frame: Up to 4 years ]
  The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated. The response rate will be calculated, in each individual cohort as supplementary.
• Disease free survival rate [ Time Frame: At 2 years ]
• Duration of response [ Time Frame: Up to 4 years ]
  The distribution of duration of complete response will be estimated using the method of Kaplan-Meier.
• Incidence of adverse events assessed by Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 4 years ]
  The maximum grade for each type of adverse event at each evaluation will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. Longitudinal analysis techniques will be utilized to determine the effect of time on treatment adverse events.
• Overall survival [ Time Frame: From registration to death due to any cause, assessed up to 2 years ]
  The distribution of survival time will be estimated using the method of Kaplan-Meier.
• Progression free survival [ Time Frame: Up to 4 years ]
  The distribution of survival time will be estimated using the method of Kaplan-Meier.
• Quality of life as measured using the Functional Assessment of Cancer Therapy-lymphoma [ Time Frame: Up to 4 years ]
  The assessment will be scored according to the scoring algorithm. Changes from baseline will be calculated at each assessment time points. Mean change scores at each time point will be calculated to determine if quality of life is reduced over the course of treatment. Longitudinal techniques will be employed to describe changes over time.
• Treatment free survival [ Time Frame: From registration to next treatment or death due to any cause, assessed up to 4 years ]
  The distribution of treatment-free survival will be estimated using the method of Kaplan-Meier.

• Radiologic analysis [ Time Frame: Up to 4 years ]
  Measurements of index lesion(s) (non-cryoablated lesion) will be evaluated over time for each patient as a marker of systemic immune and treatment response to pembrolizumab and localized treatment with cryoablation and dendritic cell therapy. The index lesion(s) will be selected by the treating physician/investigator and are noncryoablated node. The percent change from baseline in index lesion measurements will be assessed over time. Differences in values over time will be summarized descriptively and graphically. The whole body computed tomography (CT) or positron emission tomography/CT will be used to assess overall clinical response and time to progression using the standard Cheson criteria.
• Change in immunologic correlates [ Time Frame: Baseline up to 4 years ]
  Will be evaluated and summarized both quantitatively and graphically. Each of the correlative endpoints will be summarized individually, but will also be evaluated in terms of their relationships to one another; i.e., will use Spearman rank correlation coefficient to assess the correlations between baseline levels as well as between changes before and after treatment in these immunologic markers. In addition, these immunologic markers will be correlated with cancer and treatment- related outcomes (e.g. response, toxicities). Relationships will also be explored graphically using scatter plots.

• Change in immunologic correlates [ Time Frame: Baseline up to 4 years ]
  Will be evaluated and summarized both quantitatively and graphically. Each of the correlative endpoints will be summarized individually, but will also be evaluated in terms of their relationships to one another; i.e., will use Spearman rank correlation coefficient to assess the correlations between baseline levels as well as between changes before and after treatment in these immunologic markers. In addition, these immunologic markers will be correlated with cancer and treatment- related outcomes (e.g. response, toxicities). Relationships will also be explored graphically using scatter plots.
• Radiologic analysis [ Time Frame: Up to 4 years ]
  Measurements of index lesion(s) (non-cryoablated lesion) will be evaluated over time for each patient as a marker of systemic immune and treatment response to pembrolizumab and localized treatment with cryoablation and dendritic cell therapy. The index lesion(s) will be selected by the treating physician/investigator and are noncryoablated node. The percent change from baseline in index lesion measurements will be assessed over time. Differences in values over time will be summarized descriptively and graphically. The whole body computed tomography (CT) or positron emission tomography/CT will

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)

CORRELATIVE OBJECTIVES:

I. Assess the effect of combination immunotherapy on patients' immune status and anti-tumor immune response. (Phase II) II. Assess the potential association between PD-1/PD-L1/PD-L2 expression in tumor and blood with clinical efficacy. (Phase II) III. Assess the potential association between tumor antigen mutations and antigen-specific immune response with clinical efficacy. (Phase II) IV. Evaluate patient quality of life. (Phase II)

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 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive dendritic cell therapy intratumorally (IT) on days 2, 8, and 15 of cycles 2 and 3, and day 2 of cycles 4 and 5. Patients undergo cryosurgery on day 2 of cycle 2 and receive pneumococcal 13-valent conjugate vaccine by injection on day 2 of cycles 2-5. Treatment repeats every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients who are CR, PR, or stable disease (SD) after completion of therapy, may receive pembrolizumab for an additional 18 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months during the first year post-treatment, every 4 months during the second year post-treatment, and then every 6 months for up to 2 years.

• Aggressive Non-Hodgkin Lymphoma
• Indolent Non-Hodgkin Lymphoma
• Recurrent Diffuse Large B-Cell Lymphoma
• Recurrent Follicular Lymphoma
• Recurrent Mantle Cell Lymphoma
• Recurrent Marginal Zone Lymphoma
• Recurrent Non-Hodgkin Lymphoma
• Recurrent Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma
• Recurrent T-Cell Non-Hodgkin Lymphoma
• Small Lymphocytic Lymphoma

• Procedure: Cryosurgery
  Undergo cryosurgery
  Other Names:

  • Ablation, Cryo
  • Cryoablation
  • cryosurgical ablation
• Biological: Dendritic Cell Therapy
  Given IT
  Other Name: Dendritic Cell Vaccine Therapy
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Biological: Pembrolizumab
  Given IV
  Other Names:

  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475
• Biological: Pneumococcal 13-valent Conjugate Vaccine
  Given by injection
  Other Names:

  • PCV 13
  • PCV13 Vaccine
  • Prevnar 13
• Other: Quality-of-Life Assessment
  Ancillary studies
  Other Name: Quality of Life Assessment

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)
• Patients with aggressive NHL must have had >= 2 regimens; Note: This includes diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), primary mediastinal large B-cell lymphoma (PMBCL), and T cell lymphoma

• 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 or 1
• Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 14 days prior to registration)
• Absolute lymphocyte count >= 200/mm^3 (obtained =< 14 days prior to registration)
• Platelet count >= 50,000/mm^3 (obtained =< 14 days prior to registration)
• Hemoglobin >= 8.0 g/dL (obtained =< 14 days prior to registration)
• Total bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert's disease (obtained =< 14 days prior to registration)
• Aspartate transaminase (AST/serum glutamic-oxaloacetic transaminase [SGOT]) and alanine transaminase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (obtained =< 14 days prior to registration)
• Creatinine =< 1.5 x ULN or calculated creatinine clearance >= 60 mL/min for subject with creatinine ˃ 1.5 x institutional ULN (obtained =< 14 days prior to registration)
• 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 because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:

  • 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, Sjogren's disease, systemic lupus erythematosus, 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