Notification Issue Date:

Medical Policy Bulletin

Title:Personalized Vaccines (e.g. Provenge®)

Policy #:08.00.95d

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.

The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.


Coverage is subject to the terms, conditions, and limitations of the member's contract.


Sipuleucel-T (Provenge®) therapy is considered medically necessary, and, therefore covered for asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer (CRPC) when all of the following criteria are met:
  • A castrate level of testosterone (less than 50 ng/dL)
  • An Eastern Cooperative Oncology Group (ECOG) performance status of zero or one
  • A life expectancy of greater than six months
  • No hepatic metastases
  • Serum Prostate Specific Antigen (PSA) greater than or equal to 5.0 ng/mL

When considered medically necessary, Sipuleucel-T (Provenge®) is limited to three complete doses.


All other uses for sipuleucel-T (Provenge®) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

All other personalized vaccines are considered experimental/investigational and, therefore, not covered because there are no other personalized vaccines approved by the US Food and Drug Administration (FDA).


The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.


Subject to the terms and conditions of the applicable benefit contract, personalized vaccines (e.g. Provenge) are covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.


The FDA grated initial approval for the use of sipuleucel-T (Provenge®) to the Dendreon Corporation (Seattle, Washington) on April 29, 2010.


Personalized medicine is an approach that involves tailoring therapy for an individual, through the use of genetic or other physiological information unique to the individual, in order to provide timely, specific, and effective treatment options. Personalized medicine uses diagnostic tools to specifically guide individual therapy. An emerging area under personalized medicine is personalized or therapeutic vaccines.

The current practice regarding medical vaccination involves a preventative approach by administering the same set of vaccines to everyone in the population at risk to protect them from getting an illness. The understanding of vaccination is that everyone will react in a similar way immunologically, by developing protective levels of antibody, or immunity, with little or no side effects. This approach has allowed the control of many wide-spread infectious diseases, which has been the primary focus to this point.

Personalized vaccines, an emerging field of vaccinomics, targets an individual's own antigens to maximize their own immune response to a disease. Cancer vaccines, also known as a type of therapeutic vaccines, are being designed to treat existing cancers and are administered after the individual has been diagnosed with cancer.

The development of therapeutic vaccines is the result of a better understanding of how the immune system functions. T-cells recognize pathogenic antigens or peptides from either the inside of the cell or the outside of the cell. These antigens compose the human leukocyte antigen (HLA) system. The HLA system contributes significantly to the variations in immune response after vaccination. Immunotherapy is an attempt to regulate the individual's own immune responses to a disease.

There is ongoing research for therapeutic vaccines for a number of indications, with the majority of vaccines in development for potential therapies in a number of cancers. As an option for oncological therapy, these vaccines are being developed with the goals of trying to stop the growth of existing tumors, prevent cancer from recurring, or eliminate cancer cells not killed by prior treatments. These vaccines function by encouraging the individual's own immune system to recognize the cancer cells.

Generally, therapeutic vaccines expose the body's immune cells to weakened forms of antigens that are present on the surface of the disease-causing agent. This exposure causes the immune system to increase production of plasma cells that make specific antibodies, which are used by the immune system to battle a potential or existing disease. The immune system also increases production of T cells that recognize the disease-causing agent. These activated immune cells remember the exposure, so that the next time the disease-causing agent enters the body, the immune system is already prepared to respond and stop the initiation or progression of disease. Therapeutic vaccines may target different pathways of the immune system depending on the antigens being targeted, since various antigens may be displayed depending on the etiology of a disease.

While many personalized vaccines are in development, there is only one currently approved by the US Food and Drug Administration (FDA), sipuleucel-T (Provenge®).

Sipuleucel-T (Provenge®) is an autologous cellular immunotherapy product indicated for the treatment of individuals with asymptomatic, or minimally symptomatic, metastatic castrate-resistant (castration-recurrent, hormone-refractory) prostate cancer. While the precise mechanism of action is unknown, sipuleucel-T (Provenge®) is designed to induce an immune response targeted against prostatic acid phosphatase (PAP), an antigen expressed in most prostate cancers. The product consists of peripheral blood mononuclear cells (PBMCs) that are obtained from individuals by leukapheresis and activated in vitro with a recombinant fusion protein, prostatic acid phosphatase fused with granulocyte-macrophage colony-stimulating factor (GM-CSF). These activated cells, including antigen-presenting cells (APCs), are then re-infused intravenously into the individuals. During ex vivo culture with PAP-GM-CSF, APCs take up and process the recombinant target antigen into small peptides that are then displayed on the APC surface.

The US Food and Drug Administration (FDA) approved sipuleucel-T (Provenge®) (Dendreon Corporation; Seattle, Washington) via a Biologics Licensing Application (BLA) application for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer (for autologous use only) on April 29, 2010. This approval was based on a double-blind, placebo-controlled, multicenter phase 3 trial of 512 men with metastatic castration- resistant prostate cancer and an expected survival of at least 6 months. The sipuleucel-T group (n=341) had a 22% relative reduction in the risk of death compared to the placebo group (n=171), representing a 4.1 month improvement in median survival.

The FDA expressed concern in regard to the possible association of cerebrovascular events in the sipuleucel-T (Provenge®) vaccine--treated group. The FDA review called the cerebrovascular event rate a “potential safety signal” and as part of its approval will require a postmarketing study based on a registry design to assess the risk of cerebrovascular events in 1,500 individuals with prostate cancer who receive sipuleucel-T (Provenge®).

There are several other personalized vaccines in development, which are still being investigated in varying phases of clinical trials. Many of these vaccines result in new treatment options for refractory and/or advanced cancers, for which no therapeutic options have been available. However, most of them are add-ons to existing therapy regimens. Some personalized vaccines currently in development are being targeted for refractory or advanced cancers, such as melanoma, Hodgkin's lymphoma, relapsed or refractory follicular non-Hodgkin's lymphoma, and lung cancer.

While the future of therapeutic vaccination is promising, there are many elements of this emerging field to consider: up-front costs for preparation of the personalized vaccines, additional genetic testing of individuals to determine eligibility based on genetic mutations of the cancer, more time spent by professional providers explaining these options and results, potential serious or life-threatening side effects that require close monitoring, and possible further mutation of cancer cells in individuals after several months. Furthermore, because therapeutic vaccination is specific to the individual, it does not take into consideration the individual's family history, social circumstances, environment, and behaviors.

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

American Cancer Society (ACS). Immunotherapy. [ACS Web site]. 08/08/2016. Available at: Accessed October 05, 2018.

Berry DL, Moinpour CM, Jiang CS, et al. Quality of life and pain in advanced stage prostate cancer: results oa Southwest Oncology Group randomized trial comparing docetaxel and estramustine to mitoxantrone and prednisone. J Clin Oncol. 2006;24(18):2828-35.

Centers for Medicare & Medicaid Services (CMS). Decision memo for autologous cellular immunotherapy treatment of metastatic prostate cancer (CAG-00422N) [CMS Web site]. 06/30/2011. Available at: Accessed October 05, 2018.

Centers for Medicare & Medicaid Services (CMS). MLN Matters. Autologous Cellular Immunotherapy Treatment of Metastatic Prostate Cancer. [CMS Web site]. 06/30/2011. Available at: Accessed October 05, 2018.

Cookson M, Roth B, Dahm P, et al. Castration-resistant prostate cancer: AUA guideline. [AUA Web site]. 2014. Amended 2018. Available at: Accessed October 05, 2018.

Dendreon Corporation. Provenge® (sipuleucel-T) prescribing information. Seattle, WA; April

Eastern Cooperative Oncology Group. ECOG Performance Status. [ECOG Website]. Available at: Accessed October 05, 2018.

Higano CS, Schellhammer PF, Small EJ, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009;115(16):3670-9.

Kantoff P, Higano C, Shore N, et al. Sipuleucel-T immunotherapy for castration- resistant prostate cancer. New Engl J Med. 2010; 363(5); 411-422.

Microdex® Healthcare Series. Sipuleucel-T. Truven Health products. Available at: [subscription only]. Accessed October 05, 2018.

National Comprehensive Cancer Network NCCN). NCCN Clinical Practice Guidelines in Oncology - Prostate Cancer. V4.2018.[NCCN Web site]. 08/15/2018. Available at: [via subscription only].
Accessed October 05, 2018.

National Comprehensive Cancer Network (NCCN). NCCN Drugs and Biologics Compendium. sipuleucel-T (Provenge®). [NCCN Web site]. 2018. Available at: [via subscription only]. Accessed October 05, 2018.

National Institute of Health (NIH). Prostate cancer. [NCI Web site].04/30/2018. Available at: Accessed October 05, 2018.

Provenge ® (Sipuleucel-T).[prescribing information]. Seattle,WA: Dendreon Corporation. 10/2014. Available at: Accessed October 05, 2018.

Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006;24(19):3089-94.

Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-12.

US Food and Drug Administration (FDA). Approval letter for Provenge (Sipuleucel-T). [FDA Web site]. 04/29/2010. Available at: Accessed October 05, 2018.

US Food and Drug Administration (FDA). Cellular, Tissue and Gene Therapies Advisory Committee Meeting, March 29, 2007. Clinical Briefing Document: Provenge (Sipuleucel-T). [FDA Web site]. Available at: Accessed October 05, 2018.

US Food and Drug Administration (FDA). Vaccines, blood and biologics. PROVENGE (sipuleucel-T). Supporting Documents. [FDA Website]. 02/20/2018. Available at: Accessed October 05, 2018.


Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.

ICD - 10 Procedure Code Number(s)


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.

ICD -10 Diagnosis Code Number(s)

C61 Malignant neoplasm of prostate

HCPCS Level II Code Number(s)

Q2043 Sipuleucel-T, minimum of 50 million autologous cd54+ cells activated with PAP-GM-CSF, including leukapheresis and all other preparatory procedures, per infusion

Revenue Code Number(s)


Coding and Billing Requirements

Cross References

Policy History

09/25/2019This policy has been reissued in accordance with the Company's annual review process.
11/07/2018This policy became effective 07/15/2015. It has been reviewed and reissued to communicate the Company’s continuing position on Personalized Vaccines (e.g., Provenge®).

Effective 10/05/2017 this policy has been updated to the new policy template format.

Version Effective Date: 07/15/2015
Version Issued Date: 07/15/2015
Version Reissued Date: 09/25/2019

Connect with Us        

© 2017 Independence Blue Cross.
Independence Blue Cross is an independent licensee of the Blue Cross and Blue Shield Association, serving the health insurance needs of Philadelphia and southeastern Pennsylvania.