New cancer vaccine approach directly targets dendritic cells

April 16, 2014, Celldex Therapeutics
Dendritic cells present antigens to T cells so that T cells can squash infection, or cancer. Spreading tumors, like the one pictured here, can alter the microenvironment to block this immune activation. Now, researchers have developed a cancer vaccine that directly targets dendritic cells, and they show that this approach can enhance the immune response to tumors. Credit: C. Bickel/Science Translational Medicine

Celldex Therapeutics announced today that final data from its Phase 1 study of CDX-1401 in solid tumors, including long-term patient follow-up, have been published in Science Translational Medicine. The data demonstrate robust antibody and T cell responses and evidence of clinical benefit in patients with very advanced cancers and suggest that CDX-1401 may predispose patients to better outcomes on subsequent therapy with checkpoint inhibitors. CDX-1401 is an off-the-shelf vaccine consisting of a fully human monoclonal antibody with specificity for the dendritic cell receptor DEC-205 linked to the NY-ESO-1 tumor antigen. The vaccine is designed to activate the patient's immune system against cancers that express the tumor marker NY-ESO-1. While the function of NY-ESO-1 continues to be explored, references in the literature suggest that its expression might reflect the acquisition of properties that cancers find useful, such as immortality, self-renewal, migratory ability and the capacity to invade.

The Phase 1 study of CDX-1401 is the first clinical study to demonstrate that an off-the-shelf vaccine that targets dendritic cells in vivo through DEC-205 can safely lead to robust humoral and cellular immunity—overcoming a significant challenge in the development of protein based vaccines. Targeting protein antigens to the DEC-205 receptor on dendritic cells was pioneered by the late Ralph Steinman, MD, a member of Celldex's Scientific Advisory Board. Dr. Steinman received the 2011 Nobel Prize in Physiology or Medicine for his discovery of the dendritic cell and its role in adaptive immunity. This now-proven ability to target proteins, like NY-ESO-1, to dendritic cells to generate potent immune responses specific to these proteins represents a promising approach for the next generation of vaccines against pathogens and cancer.

"CDX-1401 offers a novel, well-tolerated and practical approach to generating protein specific immunity that can be readily combined with other treatment strategies to boost immunity against pathogens and tumors," said Dr. Madhav Dhodapkar, MBBS, Arthur H. and Isabel Bunker Professor of Medicine and Immunobiology, Chief of the Section of Hematology at the Department of Internal Medicine and Clinical Research Program Leader of the Hematology Program at Yale Cancer Center and lead author of the paper. "The preliminary findings in who received therapy with a checkpoint inhibitor following the vaccine provide further rationale for combination immunotherapy strategies, meriting further investigation."

Thomas Davis, MD, Senior Vice President and Chief Medical Officer of Celldex Therapeutics added, "CDX-1401 has overcome a significant historical challenge in the development of protein based vaccines by successfully targeting in vivo. It now sits at the forefront of a new generation of off-the-shelf dendritic cell targeted vaccines that we believe hold significant promise. Based on the results observed in this Phase 1 study, we expect CDX-1401 to enter at least two combination studies this year with both our own investigational therapies and external therapies in melanoma and other indications where we believe a regimen could play an important role." Initial results from the Phase 1 study of CDX-1401 were presented at the 2012 Society for Immunotherapy Annual Meeting. The manuscript published today expands upon this data and includes longer-term patient follow up.

CDX-1401 Phase 1 Study Overview and Results

The study was designed to assess the safety, immunogenicity and clinical activity of escalating doses of CDX-1401 with TLR agonists (resiquimod and/or Poly ICLC (HiltonolTM) in 45 patients with advanced malignancies refractory to all available therapies. CDX-1401 was well tolerated, with no dose limiting or grade 3 toxicities reported. The most frequently reported adverse events were administration site reaction, fatigue, nausea and chills. Treatment induced humoral and cellular immunity to NY-ESO-1 in patients with NY-ESO-1 expressing tumors across various dose levels and adjuvant combinations.

Significant anti-NY-ESO-1 titers occurred in 79% (33/42) of evaluable patients, with high titers (>1:10,000) in 52% and very high titers (>1:100,000) in 33% of patients. Similarly strong humoral immunity developed in each cohort and in patients with or without confirmed NY-ESO-1 expression in their tumor. Approximately 54% of patients with NY-ESO-1 positive tumors had anti-NY-ESO-1 titers at baseline and most increased after vaccination. NY-ESO-1-specific T cell responses were absent or low at baseline, but increased post-vaccination in 56% of evaluable patients, including both CD4 and/or CD8 T cell responses. Durability of the T cell response was demonstrated in two patients from whom samples from additional cycles of CDX-1401 treatment were available. In these patients, the induction of NY-ESO-1 specific T cells was maintained through three cycles (approximately seven months) of treatment.

Thirteen patients experienced stable disease, with a median duration of 6.7 months (2.4+ to 13.4). In addition, two patients with melanoma experienced tumor regression of about 20% shrinkage in target lesions. The detection of NY-ESO-1 expression in tumor tissue did not appear to correlate with patient outcome. Stable disease was seen in 7/27 (26%) of the patients with NY-ESO-1 expression, and in 5/15 (33%) of those lacking NY-ESO-1 expression. However, the proportion of patients with stable disease was higher for those who maintained or developed NY-ESO-1 specific T cell responses. Stable disease was seen in 3/6 (50%) patients who entered the study with pre-existing cellular immunity to NY-ESO-1, and all three had increased responses while on study. For the remaining 13 patients who developed cellular immunity while on treatment, 6 (46%) experienced stable disease. In contrast, stable disease was seen in only 2/15 (13%) patients who did not develop cellular immunity to NY-ESO-1. Interestingly, 4/6 (67%) patients that displayed the strongest responses (>50 IFNγ spots per 2 x 105 PBMC) also experienced stable disease. The association of cellular response and stable disease does not appear to be a consequence of extended duration of therapy. Peak responses were observed in the first treatment cycle for seven of the nine patients with stable disease who developed .

Of the 45 patients in the Phase 1 study, eight went on to receive subsequent therapy of either Yervoy® or an investigational checkpoint inhibitor and six of these patients had objective tumor regression. Six patients with melanoma received Yervoy within three months of treatment with CDX-1401 and four (67%) had objective tumor responses, including one complete response, which compares favorably to the overall response rate of 11% previously reported in metastatic melanoma patients treated with single-agent Yervoy. In addition, two patients with non-small cell lung cancer received an investigational checkpoint blockade within two months of completing treatment with CDX-1401 and both achieved partial responses. All six of the responding patients had tumors confirmed to express NY-ESO-1. Interestingly, five also developed NY-ESO-1-specific cellular response, while four also developed or maintained NY-ESO-1 specific humoral response, by the end of treatment with CDX-1401.

Explore further: Moffitt Cancer Center begins Phase I clinical trial of new immunotherapy

More information: "Induction of Antigen-Specific Immunity with a Vaccine Targeting NY-ESO-1 to the Dendritic Cell Receptor DEC-205," by M.V. Dhodapkar et al, Science Translational Medicine, 2014.

Related Stories

Moffitt Cancer Center begins Phase I clinical trial of new immunotherapy

April 10, 2014
Moffitt Cancer Center has initiated a phase I clinical trial for a new immunotherapy drug, ID-G305, made by Immune Design. Immunotherapy is a treatment option that uses a person's own immune system to fight cancer. It has ...

Recurrent ovarian cancers respond to cancer vaccine after 'reprogramming' with decitabine

January 3, 2014
Treatment with the drug decitabine prior to administration of chemotherapy and a cancer vaccine yielded clinical benefit for women with recurrent ovarian cancer, suggesting that this combinatorial chemoimmunotherapy may provide ...

Pox vaccines extend survival for patients with melanoma, ovarian cancer

March 26, 2012
An immunotherapy regimen incorporating poxviruses and targeting a particular tumor antigen, NY-ESO-1, has shown promise in treating two types of cancers. Kunle Odunsi, MD, PhD, Chair of the Department of Gynecologic Oncology ...

Study finds promising therapeutic target for hard-to-treat brain tumor

August 27, 2013
Johns Hopkins researchers say they have found a specific protein in nearly 100 percent of high-grade meningiomas—the most common form of brain tumor—suggesting a new target for therapies for a cancer that does not respond ...

Biomarker identifies melanoma patients who may respond to immunotherapy MK-3475

April 7, 2014
Among melanoma patients treated with the PD-1 inhibitor MK-3475, those whose tumors had the protein PD-L1 had better immune responses and higher survival rates, according to results presented here at the AACR Annual Meeting ...

Recommended for you

Enzyme inhibitor combined with chemotherapy delays glioblastoma growth

January 23, 2018
In animal experiments, a human-derived glioblastoma significantly regressed when treated with the combination of an experimental enzyme inhibitor and the standard glioblastoma chemotherapy drug, temozolomide.

'Hijacker' drives cancer in some patients with high-risk neuroblastoma

January 23, 2018
Researchers have identified mechanisms that drive about 10 percent of high-risk neuroblastoma cases and have used a new approach to show how the cancer genome "hijacks" DNA that regulates other genes. The resulting insights ...

Scientists block the siren call of two aggressive cancers

January 23, 2018
Aggressive cancers like glioblastoma and metastatic breast cancer have in common a siren call that beckons the bone marrow to send along whatever the tumors need to survive and thrive.

Researchers identify a protein that keeps metastatic breast cancer cells dormant

January 23, 2018
A study headed by ICREA researcher Roger Gomis at the Institute for Research in Biomedicine (IRB Barcelona) has identified the genes involved in the latent asymptomatic state of breast cancer metastases. The work sheds light ...

Boosting cancer therapy with cross-dressed immune cells

January 22, 2018
Researchers at EPFL have created artificial molecules that can help the immune system to recognize and attack cancer tumors. The study is published in Nature Methods.

Workouts may boost life span after breast cancer

January 22, 2018
(HealthDay)—Longer survival after breast cancer may be as simple as staying fit, new research shows.

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

wealthychef
not rated yet Apr 16, 2014
Can someone translate this for me? What does "stable disease" mean? Did the patients improve or not? Did they live longer, feel better?

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.