Adoptive Immunotherapy

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General Background
Adoptive immunotherapy, also called adoptive cellular therapy, is the transfer of immune cells with antitumor activity into a patient to mediate tumor regression. The therapy involves the removal of lymphocytes (white blood cells) from an individual, stimulation of those lymphocytes to increase their immune capabilities, and the transfer of those cells back into the patient. T-Cells, B-Cells and NK cells are types of lymphocytes. The potential benefit of this therapy depends on the availability of recombinant human cytokines and the ability to collect large enough quantities of stimulated lymphocytes for therapeutic transfer. Cytokines are cell signaling protein molecules that aid cell to cell communication in immune responses and stimulate the movement of cells towards sites of inflammation, infection and trauma. Examples of cytokines include interleukin and interferon which aid in regulating the immune system's response to inflammation and infection.
Adoptive immunotherapy has been proposed as a treatment option for numerous conditions including cancer, human immunodeficiency virus, type I diabetes mellitus and rheumatoid arthritis. Several techniques have been investigated, including the use of lymphocyte activated killer (LAK) cells, tumor Infiltrating lymphocytes (TILs), and T-cell lymphocytes/dendritic cells (DCs). At the present time, the high-dose bolus IL-2 regimen remains the treatment of choice for appropriate patients with access to such treatment and is the gold standard to which other IL-2-based regimens should be compared. The addition of tumor-infiltrating lymphocytes, other cytokines, or chemotherapeutics have failed to improve on the durable partial and complete responses observed with highdose IL-2 treatment.

Lymphocyte Activated Killer (LAK) Cells
LAK cells are developed by removing peripheral blood lymphocytes and stimulating them with high concentrations of interleukin 2 (IL-2), a cytokine produced by lymphocytes that stimulates both T-cells and natural killer cells. Once there is a large enough quantity of stimulated cells, the cells are transferred back into the patient. Studies have suggested that LAK cells are limited in therapeutic efficacy and have demonstrated no advantage for the administration of LAK plus IL-2 over administration of IL-2 alone (Kasslin, 2014). Newer concepts in tumor immunology have lessened the importance of the continuing debate over the merits of IL-2/LAK therapy. The role of this therapy has not been established for any indication.
Literature Review: There is insufficient evidence to demonstrate the safety and effectiveness of adoptive immunotherapy with lymphocyte activated killer cells for the treatment of any condition, including malignancy and human immunodeficiency virus. Studies have primarily been in the form of case series with small patient populations (n=17-33) (Dillman, et al., 2009;Thionuun, et al., 2002). Kimura et al. (2018) reported on the final results of a phase III, randomized control (RCT) investigating postsurgical adjuvant chemotherapy plus immunotherapy (group A) (n=50) vs. chemotherapy alone (group B) (n=51) for the treatment of non-small cell lung cancer (NSCLC). The trial was first reported by Kimura et al (2015). The objective of the continued research was to evaluate how long immunotherapy in combination with adjuvant chemotherapy or molecular targeted therapy improved the prognosis in post-surgical advanced lung cancer patients with poor prognosis. The authors noted that the target of immunotherapy in this trial was not the primary lesion, but the undetectable tumor cells remaining after the resection of primary carcinoma of the lung. Patients were age < 76 years; Eastern Cooperative Oncology Group performance status 0 or 1; with adequate liver, renal and bone marrow function; primary NSCLC histology (including combined type small cell carcinoma); and pathological of stage IB with tumor sizes larger than five centimeters or with severe vessel invasion and stages II-IV (including non-curative resection cases). Patients were excluded if they had exploratory thoracotomies or macroscopic residual tumors. Immunotherapy was comprised of the adoptive transfer of autologous activated killer T cells and dendritic cells (AKT-DC) from the patient's own regional lymph nodes. Group A received AKT-DC intravenously one week after each course of chemotherapy, once a month for the first six months after resection and then every two months for two years after surgery. Group B was the control group who received chemotherapy alone. Primary outcomes measured were overall survival (OS) rate and recurrence-free survival and pathological of stage IB with tumor sizes larger than five centimeters or with severe vessel invasion and stages II-IV. Non-curative resection cases were included. Immunotherapy consisted of the adoptive transfer of autologous activated killer T (AKT) cells and dendritic cells (DC) obtained from the patients' own regional lymph nodes. The autologous AKT-DC from the regional lymph nodes of patients had to grow enough to provide more than 7 × 10 9 cells for each course of the therapy. Undetectable tumor cells remaining after the resection of the primary tumor were the target of the immunotherapy. Group A received 12-15 courses of treatment over a two-year period and group B received four courses of chemotherapy. Stage IIIA patients received two courses of induction chemotherapy prior to surgery. Follow-ups occurred for up to five years. The primary end point was overall survival with recurrence-free survival, toxicity, and adverse effects of immunotherapy as secondary end points. The two-year overall survival rates in groups A and B were 93.4% and 66.0%, and the five-year rates were 81.4% and 48.3%, respectively, statistically significant in favor of group A (p=0013). The two-and five-year recurrence-free survival rates were also statistically significant in favor of group A (p=0.0020). Adverse events included chills, shivering and fever. There were 19 cases of recurrence in group A and 33 cases in group B. Thirty-five stage IIIB and IV patients were excluded from the study because macroscopic residual tumors remained after surgery, and enough T cells could not be obtained for dosage. Limitations of the study include the small patient population, heterogeneity of the disease stages and lack of sufficient numbers of lymphocytes obtained from patients with stage N2 and N3. Additional data from a large-scale multi-center RCT is needed before the clinical importance of this therapy is determined. The most effective dose for immunotherapy in this population has not been determined.

Tumor Infiltrating Lymphocytes (TILs)
Tumor tissue contains its own immune system cells called tumor infiltrating lymphocytes. In TIL therapy, tumor infiltrating lymphocytes are removed from the tumor itself and treated with IL-2. These activated cells are then returned to the patient to attack the tumor (American Cancer Society [ACS], 2015). There is insufficient evidence to support the safety and effectiveness of adoptive immunotherapy using tumor infiltrating lymphocytes for the treatment of any condition including melanoma and renal cell cancer. Study populations were small and heterogeneous, and outcomes related to overall survival are variable. At this time, the role of this therapy has not been established for any indication.
Literature Review: Rosenberg et al. (2011) reported on a trial of 93 patients with measurable metastatic melanoma who were treated with the adoptive transfer of autologous TILs administered in conjunction with interleukin-2 following a lyphodepleting preparative regimen on three sequential clinical trials. Ninety-five percent of the patients had progressive disease following prior treatment. About 85% of study participants had surgically resectable disease. Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) in the three trials using chemotherapy alone or with two or 12 Gy irradiation were 49%, 52%, and 72%, respectively. Twenty of the 93 patients (22%) achieved complete tumor regression, and 19 have ongoing complete regressions beyond three years. The actuarial three-and five-year survival rates for the entire 93 patients were 36% and 29%, respectively. For the 20 complete responders, three-and five-year survival rates were 100% and 93%, for the 32 partial responders 31% and 21%, and for the 41 non-responders were 7% and 5%, respectively. Overall follow-up was 62 months. Limitations of the study are the uncontrolled design and lack of comparator. Dreno et al. (2003) conducted a randomized controlled trial to demonstrate the use of TILs as adjuvant therapy for stage III (metastasis to regional lymph nodes) melanoma. After lymph node excision, patients without any detectable metastases were randomly assigned to receive a two-month course of either TIL plus IL-2 or IL-2 only. The primary endpoint was the duration of the relapse-free interval. Eighty-eight patients eligible for treatment were enrolled in the study. After a median follow-up of 46.9 months, the analysis did not show a significant extension of the relapse-free interval or overall survival for the study population. Khammari et al. (2007) reported long-term results of the Dreno study. After a median follow-up of 114.8 months, there was no change in the non-significant extension of relapse free interval or overall survival.

T-Cell Lymphocytes/Dendritic Cells (DCs)
T-cell (also known as dendritic cell [DC]) adoptive immunotherapy involves isolating the DCs, harvesting and exposing the cells to a variety of immunologic stimuli, then re-infusing the cells back into the patient. This process is also called autolymphocyte therapy. Phase I and II trials have explored the use of DCs in treating hormone-resistant prostate cancer. The studies reported that therapy was well-tolerated and resulted in a reduction of prostate-specific antigen (PSA) levels. The role of antigen-loaded dendritic cells has also been explored for the treatment of other malignancies (e.g., lymphoma, myeloma, subcutaneous tumors, melanoma, renal cell, uterine, cervical and non-small cell lung cancer) and autoimmune disorders, such as type I diabetes mellitus and rheumatoid arthritis.
Overall, the benefit of DCs to health outcomes has not been established for most indications. Exceptions include Sipuleucel-T (Provenge ® ) (see Cigna Coverage Policy Oncology Medications) Randomized controlled trials are needed to determine safety and effectiveness, patient eligibility criteria, and treatment protocols, including optimal dosing, route of delivery, and source of antigens for the treatment of other malignancies and autoimmune disorders, including type I diabetes mellitus and rheumatoid arthritis. All studies used mature DCs, different antigen-loading methods and different injection routes (intravenous, intradermal, subcutaneous and intra-tumoral). The number of injection times ranged from 1-7 and the number of cells ranged from 4x10 6 to 2x10 10 . The control groups were those patients who would not accept DC vaccine or DC-CIK. Primary outcomes measured were immunologic changes including CD4+ T/CD8+ T ratio, progression free survival (PFS) rate, overall survival (OS) rate, median PFS time and median OS time. Outcome results reported statistically significant improved CD4+ T/CD8+ T ratio (p<0.001), increased one-year, 18-months and five-year PFS rate (p<0.05) and OS rate (p<0.05). Median PFS time was 1.98 times that of control (p<0.001) and median OS time was 1.72 times that of control (p<0.001), both statistically significant. Adverse reactions were low-grade fever, skin reaction, myalgia, shiver, vomiting, hyperpyrexia, and fatigue. Author reported limitations included: small patient populations; heterogeneity of the study designs and intervention methodology; and variations in the timing of medication, cell dose and the number and route of administration of treatments. Patient selection criteria for this therapy has not been established. Studies have reported that DC immunotherapy is not effective for every patient. Additional welldesigned, multi-center randomized controlled trials with large patient populations per study are needed to confirm the safety and efficacy of this treatment. these studies exceeded 1.0x10 9 . The comparator was chemotherapy alone (n=597 patients). Primary outcomes were hazard ratio (HR), overall survival (OS) rates, disease-free survival (DFS) rates and immune function. A small HR value indicates a better therapeutic effect and a HR <1 indicates lower risk. Length of follow up was five years. The survival status in the treatment group was significantly better than that in the control group with an HR of 0.712 for OS and HR of 0.66 for overall DFS. The treatment group had higher OS and DFS than the control group at both three and five years follow up. Immune function was evaluated by comparing changes in T lymphocytes before and after treatment. The number of CD3+, CD4+, CD4+/CD8+, and NK cells in patients of the treatment group were reported to be significantly increased. Adverse events were fever, chills, rashes, headaches, and nausea. Limitations of the study include the small heterogeneous (e.g., tumor state I-IV) patient populations, differences in the use of immune cells, and heterogeneity of the chemotherapy and surgical procedures. Patient selection criteria for post-surgical adjuvant chemotherapy plus immunotherapy have not been established. Additional multicenter randomized control trials with large patient populations are needed to verify efficacy of this therapy.
Xiao et al. (2018) conducted a meta-analysis to evaluate whether DC-CIK therapy repairs and reconstructs the antitumor immunity and improves the tumor responses, reveals its optimal usage and combination with chemotherapy, and provides the optimal evidence for individualized immunotherapy for non-small cell lung cancer (NSCLC). A total of 28 randomized control trials (n=2242 patients) met inclusion criteria. Inclusion criteria were: diagnosis with NSCLC using histopathological and cytological diagnostic criteria and TNM staging system; adequate kidney and liver function; and no other therapy including surgery, radiotherapy, CIK cells alone, traditional Chinese medicines, monoclonal antibody, or other cell therapies. Exclusion criteria included: duplicate studies patent, generic, abstracts, and reviews without specific data; in vitro or animal studies; studies about other tumors or nursing; studies with CIK cells or DC-CIK alone; and studies with DC-CIK plus radiotherapy, Chinese herbs, targeted therapy, surgery, or other cytotherapy. Studies with DC-CIK in two groups; nonrandomized controlled studies; and unrelated systematic reviews or meta-analysis; studies without data of peripheral blood lymphocytes were also excluded. The experimental groups were DC-CIK plus chemotherapy.

DC-CIK therapy included DC-CIK cells and Ag-DC-CIK cells (n=1127). The control groups received chemotherapy alone without restrictions on the type of chemotherapy used (n=1115). The primary outcome measured was antitumor immunity using the peripheral blood lymphocytes that included T lymphocyte subsets and natural killer cells (NK cells). T lymphocyte subsets were measured by using the proportions of CD3+ T cells, CD3+ CD4+ T cells, CD3+ CD8+ T cells, CIK cells (CD3+ CD56+ cells), and regulatory T cells (CD25+ CD4+ T cells, Treg cells) and the ratio of CD4+/CD8+ T cells. The secondary outcome was the tumor responses
and was measured using the objective response rate (ORR) and disease control rate (DCR). Length of followups ranged from one to four months after treatment. Antitumor immunity showed statistical significance in all of the study group subsets compared to the control groups: with DC-CIK immunotherapy group compared to that of the chemotherapy alone group (p=0.02); however, the two-year OS was not significantly different between groups p= 0.21). Likewise, one-year progression-free survival (PFS) was significantly prolonged in the DC-CIK immunotherapy group compared to the chemotherapy alone group (p= 0.005); however, there was no significant difference in two-year PFS (p=0.10). Partial response (PR), overall response rate (ORR) and disease control rate (DCR) were considered to assess treatment efficacy. Analysis of the DCR showed significant improvement for the group receiving combination treatment (p=0.06), but no statistically significant improvement between groups was noted for PR (p=0. 22) or ORR (p=0.76). Although data suggest short-term improvement in OS and PFS, longer-term outcomes do not reflect sustained benefit. Additional studies reflecting long-term benefit of DC immunotherapy are needed to establish the role of this therapy for the treatment of NSCLC. Draube et al. (2011) performed descriptive analyses at a study level and individual patient data level on twentynine studies involving the use of immunotherapy with mature monocyte derived dendritic cells or immature monocyte derived dendritic cells in 906 patients with prostate or renal cell cancer (RCC). Three studies were randomized phase II studies; the remaining studies were phase I/II. Analysis at study data level revealed that dendritic cell (DC) vaccination led to an antigen-specific cellular immune response in 77% of patients with prostate cancer and 61% of patients with RCC. Specific humoral immune response was detected in 55% of patients with prostate cancer and no patients with RCC. Overall, objective response (complete response + partial response+ mixed response) was observed in 7.7% of patients with prostate cancer and in 12.7% of patients with RCC. The authors concluded that results demonstrated an association between specific cellular immune response and clinical benefit in both prostate cancer and RCC trials. However, there was heterogeneity regarding DC purity and dose, DC subtype, antigen delivery, route of vaccination and quality controls between the studies. DC immunotherapy warrants further investigation in phase III randomized trials.
Kumura et al. (2008) evaluated the efficacy and toxicity of adjuvant chemo-immunotherapy using autologous dendritic cells and activated killer cells obtained from tissue cultures of tumor-draining lymph nodes for the postsurgical treatment of primary lung cancer (n=28). All patients received four courses of chemotherapy along with immunotherapy every two months for two years. Two and five-year survival rates were 88.9% and 52.9%, respectively. The authors concluded that adoptive transfer of activated killer cells and dendritic cells from the tumor-draining lymph nodes of primary lung cancer patients is safe and feasible, and that a large-scale multiinstitutional study is needed to evaluate the efficacy of this treatment.

Systematic Review of Multiple Adoptive Immune Cells
Hepatocellular Cancer: Zhao et al. (2018) conducted a systematic review and meta-analysis to evaluate the safety and efficacy of adoptive immunotherapy (AIT) for patients with hepatocellular carcinoma (HCC). AIT using lymphokine-activated killer (LAK) cells and cytokine-induced killer (CIK) cells are proposed therapies for HCC following curative treatment. Recurrence rate and mortality were the primary outcome measures. Studies were included if they met the following criteria: (a) were a randomized controlled trial (RCT) comparing patients receiving AIT to patients who did not; (b) patients received curative treatment before immunotherapy; (c) patients received otherwise similar treatments both in AIT and non-AIT arms; and (d) the study showed estimating risk ratios (RRs) with 95% confidence intervals. Eight RCTs (n=964) met inclusion criteria. All patients had undergone hepatic resection prior to receiving AIT. Five trials (n=685) used CIK, two trials (n=43) used LAK plus interleukin-2 (IL-2), and one study used transcatheter arterial chemoembolization (TACE) and LAK plus IL-2. The overall analysis showed that AIT treatment significantly decreased the one-year (p<0.00001), two-year (p<0.00001), and three-year (p= 0.0001) recurrence rate (RR). Data also showed a significant decrease in mortality at the one-year (p=0.00001), two-year (p<0.00001) and three-year (p=0.03) follow-ups. The groups treated with lymphokine-activated killer (LAK) cells showed lower pooled RR values compared to those treated with cytokine-induced killer cells. However, AIT treatment failed to affect the five-year recurrence rate and mortality (p>0.05). The most frequent reported adverse events were fever and chills. Additional rare adverse events included myalgia, headache, dizziness, fatigue, and nausea. Adverse events varied with the type of AIT received. No serious adverse events were reported. Author noted limitations of the studies included the small patient populations (n=12-112), short-term follow-ups, heterogeneity of tumor size and hepatitis B/C infection and lack of information on the clinic random allocation concealment process. It was also noted that all studies were from Asian countries and therefore, the results may not be generalizable. Larger randomized controlled studies for the various types of AIT therapies for the treatment of postoperative HCC are needed to confirm results of this analysis. Eight studies reported that adjuvant AIT significantly improved disease free survival (DFS) or progression-free survival (PFS) (p< 0.05). One small RCT and two retrospective studies reported that adjuvant AIT significantly improved overall survival (OS) (p<0.05). Meta-analysis for the RCTs (n=483) showed significant recurrence benefit of AIT at one year, two years and three years (p<0.05, each) but not at five years. Adverse events included: fever, chills, headache, nausea, myalgia, fatigue, dizziness, itching and tachycardia. All events were grade 1 or 2 and self-limiting. Five patients delayed or stopped treatment due to persistent fever. No hospital deaths or serious adverse events were reported. Limitations of the studies include: short-term follow-up; heterogeneity of the type of AIT and treatment regimen (e.g., route of administration, number of cycles used); outcomes reported varied by studies and some were conflicting; lack of reporting procedures for randomization or allocation concealment; limited data on some outcomes; and lack of external validity of the result for populations other than Asian. The authors stated that these results should be viewed with caution.
Non-small Cell Lung Cancer: Zhao et al. (2017) conducted a systematic review and meta-analysis to evaluate adoptive immunotherapy (AIT) for the treatment of non-small cell lung cancer (NSCLC). Thirteen randomized controlled trials and two observational studies met inclusion criteria. Regarding pre-treatment, seven studies included pre-surgical patients, two studies included patients treated with chemotherapy, and one study included patients treated with surgery or chemotherapy or radiotherapy. Regarding AIT regimen, three studies used lymphokine-activated killer cells (LAK) plus IL-2 (or rIL-2), seven studies used dendritic cells/cytokine-induced killer cells (DC/CIK), two studies used CIK alone, two studies used activated killer T cells (AKT) alone, and one study used tumor infiltrating lymphocytes (TIL) alone. The regimen included > 4 cycles in eight studies and ≤ 4 cycles in four studies. The precise cycle used was not identifiable in the remaining studies. Compared to the control therapy group, the AIT group exhibited significantly better overall survival (OS) rates as follows: a) oneyear (fifteen studies; n=1684) (p=0.001) b) two-years (13 studies; n=1548) (p<0.001) c) three-years (ten studies; n=1266) (p<0.001) and d) five-years (six studies; n=925) (p=0.032). AIT groups also showed significantly better progression-free survival (PFS) rates at one-year (five studies; n=519) (p<0.001), and two-years (three studies; n=353) (p=0.029). The difference in the objective response rate (ORR) (four studies; n=323) (p=0.293) and the disease control rate (DCR) (four studies; n=323) (p=0.123) were not significant between the groups. Subgroup analysis for one and two-year OS showed that CIK and DC/CIK significantly enhanced survival compared with LAK plus IL-2. Author-noted limitations included: heterogeneity of the studies and variation in the AIT cycles precluding a determination of the appropriate duration of AIT for maximum effectiveness; lack of reporting of adverse events (n=four studies); and the number of studies included were not adequate to yield credible results. All the studies included Asian participants, except for one which limits generalizability. Also, all the studies used AIT in combination with chemotherapy or radiotherapy making it difficult to estimate the efficacy of AIT alone. Further multicenter randomized controlled trials are needed to identify the clinical effectiveness of AIT and which therapy is associated with the greatest efficacy.
Zhu et al. (2017) conducted a Cochrane systematic review of the literature to evaluate the safety and effectiveness of immunotherapy (excluding checkpoint inhibitors) in patients with localized non-small cell lung cancer (NSCLC) (stages I to III) who received surgery or radiotherapy with curative intent. Included studies were randomized controlled trials, patients age ≥ 18 years, with histology confirmed NSCLC after surgical resection and patients with unresectable locally advanced stage III NSCLC who had received radiotherapy with curative intent. Nine randomized controlled trials (n=4940) met inclusion criteria. Immunological interventions included: Bacillus Calmette-Guérin (BCG), adoptive cell transfer (i.e. transfer factor, tumor-infiltrating lymphocytes, dendritic cell-cytokine induced killer), and antigen-specific cancer vaccines (melanoma-associated antigen 3 [MAGE-A3} and L-BLP25). Meta-analysis showed no statistically significant improvement in overall survival (p=0.35) or progression-free survival (p=0.19) with immunotherapy. There was no statistically significant increased risk in adverse events. In conclusion, the data do not support a clinical benefit of the use of immunotherapy for patients with localized NSCLC (stages I to III). Qian et al. (2016) conducted a systematic review and meta-analysis of studies that compared chemoradiotherapy alone to chemoradiotherapy plus adoptive immunotherapy for the treatment of non-small-cell lung cancer (NSCLC). Seven articles met inclusion criteria. The articles included clinical trials that investigated the treatment of NSCLC with adoptive immunotherapy with a mean follow-up longer than two years. Outcomes included: death, tumor recurrence, or metastasis. Studies with a sample size of less than 20 subjects were excluded. There was no significant difference in the two-year progression-free survival (PFS) in the combination of adoptive immunotherapy group and the chemoradiotherapy-alone group (p=0.284). The addition of immunotherapy did improve the two-year overall survival rate (p<0.001) of early stage NSCLC patients (p<0.01) but not for patients with advanced disease (p=0.057). Self-limited adverse effects of immunotherapy included: fever, shivers, nausea, fatigue and retention of water and sodium. Limitations of the studies include: the heterogeneity of the types of adoptive immune cells (LAK, TIL, CIK, cytotoxic T lymphocyte, γδ T cells); the combination regimen of the cells; and the short-term follow-ups. The authors noted that multicenter randomized controlled trials with large patient populations are needed to provide reliable data on which to develop guidelines for clinical practice.

Professional Societies/Organizations American Cancer Society (ACS):
In a statement regarding tumor infiltrating lymphocyte (TIL) therapy, the ACS noted that some early studies have been promising, but its use may be limited due to the inability to get TILs from patients. Treatments using TILs are being tested in clinical trials in patients with melanoma, kidney cancer, ovarian cancer, and other cancers (ACS, 2015).

National Comprehensive Cancer Network ® (NCCN ® ):
In the 2019 NCCN Guideline ® on hepatobiliary cancers NCCN states that data are currently too preliminary for the panel to provide specific recommendations regarding immunotherapy treatment in an adjuvant setting.
The 2019 NCCN Guideline ® on non-small cell lung cancer does not include any information regarding the use of adoptive immunotherapy.

Use Outside of the US
Adoptive immunotherapy is noted to be of research interest in the published, peer-reviewed scientific literature.

Coding/Billing Information
Note: 1) This list of codes may not be all-inclusive.
2) Deleted codes and codes which are not effective at the time the service is rendered may not be eligible for reimbursement.

Considered Experimental/Investigational/Unproven when used to report the adoptive immunotherapy techniques listed in this Coverage Policy for any indication:
CPT ® * Codes Description 38999 Unlisted procedure, hemic or lymphatic system HCPCS Codes Description S2107 Adoptive immunotherapy, i.e., development of specific anti-tumor reactivity (e.g., tumorinfiltrating lymphocyte therapy) per course of treatment *Current Procedural Terminology (CPT ® ) ©2018 American Medical Association: Chicago, IL.