Cancer is “the emperor of all maladies,” as Pulitzer Prize-winner Siddhartha Mukherjee put it. We have been walking, running, wearing ribbons, and donating to research on cancer for decades. While there has been great progress in the battle for a cure, there are still too many casualties every day. There isn’t anyone I know who has not been impacted by cancer. It took my mother when I was only 5 years old so I’m particularly invested. 

The struggle between life and anti-life is a tale as old as time. Fossilized tumors more than 70 million years old have been discovered to have plagued dinosaurs in prehistoric times. The Egyptians were the first to document the disease, as far back as 1600 BC, and evidence can be seen in some of their ancient mummies riddled with disseminated tumors.1

We’ve waged war against cancer for as long as we’ve existed on this planet and thanks to science, great hurdles have been cleared in our own lifetimes. Nonetheless, we are still eagerly waiting for a real breakthrough. “The emperor” will claim many more lives before it is assassinated, but it will be science to hold the smoking gun. 

Researchers in Hodgkin lymphoma are conducting ambitious clinical trials that have the potential to produce the next medical marvel: a cancer vaccine. Hodgkin lymphoma was ranked 8th on the National Cancer Institute’s list of funded research by budget in 2021 and is ripe for a major breakthrough.2 Let’s talk about why I believe this.

But first, you might say “This isn’t groundbreaking technology, this has been done before. Don’t we have Gardasil® to prevent cervical cancer?” 

Yes, Gardasil prevents cervical cancer by providing immunity to oncogenic HPV serotypes and prevents cancer by these serotypes with almost 100% effectiveness.3 The idea is to prevent cancer by preventing infection. This is an indirect approach to preventing cancer and not a true cancer vaccine.

The vaccines under investigation for diffuse large B-cell lymphoma (DLBCL) are what I would call true cancer vaccines once released. The premise is to train the immune system to recognize the molecular signature of neoplastic cells and destroy them using innate defense mechanisms.

Training the Body to Recognize Neoantigens

DLBCL is the most common type of non-Hodgkin lymphoma (NHL), which arises from genetic mutations to proto-oncogenes and tumor suppressor genes in B cells in various stages of their development.4

Standard therapy for DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy; however, up to 45%-50% of patients will relapse.5 Thanks to modern medicine, patients who relapse are not entirely out of options.

Read more about treatment of DLBCL

It is somewhat surreal to be living in a time when chimeric antigen receptor T-cell (CAR-T) therapy has become mainstream. What an unbelievable idea this was just a few years ago. How inspirational were the documentaries of the first-in-human trials to a young professional such as myself watching brave volunteers put everything on the line for the sake of others? Today, thanks to their bravery and selflessness, there are 3 CAR-T cell products approved by the US Food and Drug Administration for the treatment of refractory DLBCL, and several others in development.5 Complete response rates vary from 40% to 54%.5 

Presently, considerable advances in science have allowed for some exciting ideas in the clinical trials domain: therapeutic vaccines that train the body to recognize neoantigens. Our immune system would prevent cancer in a similar way that it prevents hepatitis B in a fully vaccinated person. It’s worth underscoring that the vaccines under investigation are meant to train the body to recognize relapses. In other words, they do not prevent DLBCL in naïve individuals, or at least not yet.

Let’s discuss the concept further. The therapeutic vaccines under investigation fall into 1 of 2 categories: autologous or allogeneic. 

Autologous Therapeutic Vaccines for DLBCL

Autologous therapeutic vaccines use autologous lymphoma cells (ie, obtained from the same patient) to generate a T-cell response against neoantigens.6 It turns out that vaccination with autologous cells alone does not produce an adequate response, so researchers combine the vaccine with autologous tumor-pulsed dendritic cells (an antigen-presenting cell [APC] that has been loaded with tumor antigens) and immunological adjuvants (components that strengthen the immunogenicity of a vaccine) to enhance the therapeutic immune response.6,7

These vaccine adjuvants stimulate APCs through Toll-like receptor (TLR) 9 but have the undesirable effect of also stimulating lymphoma B cells. The solution to this problem is to coadminister them with hydroxychloroquine, which inhibits B cell stimulation while preserving the APC enhancement.6,8 Adjuvants also contain synthetic Flt3 ligand (which mobilizes dendritic cells), GM-CSF (which stimulates growth and functions of granulocytes and cells of the macrophage lineage), and heat shock proteins (HSP), mainly gp96, HSP70 and HSP90.6,8

There are promising results from a recent phase 1/2 clinical trial conducted in patients with mantle-cell lymphoma, a type of NHL considered incurable at the time.9 Patients in this study were treated using immunotherapy then vaccinated using an autologous vaccine containing activated tumor cells. Subsequently, vaccine-primed lymphocytes were collected and reinfused after a standard autologous stem cell transplantation (ASCT).

Remarkably,  89% of patients achieved freedom from minimal residual disease at one year following ASCT, which was the primary endpoint of the study. One factor appeared to be the main determinant of treatment responsiveness: PD-L1 tumor expression. Patients with high levels of tumor PD-L1 were less likely to generate an appropriate T-cell response and were less likely to respond to therapy. The time to progression among patients who did not achieve an appropriate T-cell response was 5.8 years. Meanwhile, patients with an adequate T-cell response never progressed over an 8-year follow-up period.9 

In situ vaccination

Another approach to treatment is to inject immunologic adjuvants directly into a tumor or cancerous lymph node. A phase 1/2 trial is currently recruiting patients with NHL, metastatic breast cancer, or head and neck cancers to determine if radiation plus in situ vaccination with Flt3L/CDX-301 (a growth factor for immune cells, particularly dendritic cells), Poly-ICLC (an immune cell activation factor), and pembrolizumab (an FDA-approved monoclonal antibody used to treat various cancers but not approved for NHL).10,11 The trial is expected to end in 2026. 

While I have your attention, I’d like to make a special mention of one of my favorite potential candidates. It’s a special mention because it’s not truly a vaccine as it does not protect against relapses. It’s more of an intralesional, highly sophisticated, antineoplastic therapy that seeks to deploy small interfering RNA (siRNA) in an intratumoral injection to halt cancer growth and stimulate immune cell intratumoral infiltration and immune cell activation.12 It is currently recruiting and only in phase 1 so the main goals are to establish a safe and effective dose for phase 2 trials, but the hypothesis is fascinating.

Using siRNA, it is possible to destroy mRNA that codes for abnormal cellular membrane receptors that allow cancer cells to proliferate and infiltrate. The process is called posttranscriptional gene silencing—a mechanism that was only a theory before 2015.13 It’s exciting to see an invigorated generation of research employing bleeding-edge technology in pursuit of a cure. Hopefully, you’re beginning to understand why I believe we are due for a major breakthrough before the end of the decade. There are so many horses in the race, it’s just a matter of time. 

Autologous dendritic cell vaccine

Another strategy, currently under investigation in a phase 1/2 trial, will harvest autologous dendritic cells and incubate them with killed, autologous tumor cells and GM-CSF ex vivo. These cells will then be reinfused as a vaccine and coadministered with pembrolizumab at specific intervals. Patients will also undergo cryosurgery to remove any resectable tumors during the study period. Researchers are optimistic that this approach may be a superior treatment for NHL, including DLBCL.14 Results are expected to be released in July 2023.

Allogeneic Therapeutic Vaccines 

Allogeneic vaccines are vaccines that target tumor-specific or tumor-associated antigens highly associated with the malignancy in question—sort of like the DTaP vaccine but replacing toxoid antigens for those of cancer. They have a few major advantages: (1) they can be readily produced with a large yield, (2) low toxicity, (3) simple characterization, and (4) compatibility with other treatments.6

I like the example of the DTaP vaccine because scientists currently developing therapeutic vaccines for DLBCL are facing the same challenges encountered in the 1970s and 1980s. The DTaP vaccine was developed after its predecessor (DTP) which used whole pertussis cells (analogous to whole autologous cancer cells in our example) was criticized for its high side effect profile. So much so that it was phased out in some countries due to unproven claims that it caused sudden infant death syndrome (and that didn’t go well).15 

The acellular pertussis version (DTaP) was released in the late 1980s and became commonplace in the US in the 1990s, but there was a catch. Immunity waned over time and children began getting sick a few years after immunization.15 This is the problem we face with allogeneic DLBCL vaccines today. The current approach to the problem is to ensure high immunogenicity of vaccines using potent adjuvants and carrier delivery systems. This is of monumental importance because if a potent immune response is not generated, the vaccine has potential to do serious harm, resulting in tolerance rather than specific antitumor immunity.6 

Tumor-associated antigens that are potential targets for allogeneic vaccines are CD20 and survivin. Other potential antigens are being proposed as targets for future vaccines but there has been no development to date. 

A completed phase 1 trial vaccinated lymphoma patients with a plasmid DNA vector expressing a xenogeneic extracellular domain of CD20, but the results were never shared and remain unavailable.16 It was frustrating to find out the same is true of a completed study of a survivin vaccine (DPX-Survivac).17 The study is completed but no results have been shared.

Another trial is underway, though. It is a phase 2 trial for adults with refractory DLBCL in which participants will receive DPX-Survivac and pembrolizumab for up to 1 year. The vaccine contains a survivin-based HLA-class I synthetic peptide, a tetanus toxin universal T helper epitope A16L (carrier protein), and a proprietary adjuvant encapsulated in liposomes.18 It hopes to piggyback on the positive results of the SPiReL study—a completed phase 2 study of DPX-Survivac plus low-dose cyclophosphamide and pembrolizumab. Clinical benefit was evident in 87.5% of patients in the trial, with 25% of patients achieving a complete response and 37.5% achieving a partial response.19 

A Second Shot at Life

Something special is brewing in a research lab somewhere. There is a compelling case to be made that we will see a breakthrough before the end of the decade. The headline could read “Cancer Vaccines Now a Reality.” For those of us who have lost someone to cancer, it will be a bittersweet moment. Exaltations will resonate in the streets and in lecture halls.

“The emperor is dead!”, they will proclaim.

If only the fallen could be there to see its corpse. 

References

1. Faguet GB. A brief history of cancer: age-old milestones underlying our current knowledge database. Int J Cancer. 2015;136(9):2022-2036. doi:10.1002/ijc.29134

2. 2021 NCI Budget Fact Book – Research Funding – NCI. Published May 10, 2022. Accessed September 4, 2022.

3. Human papillomavirus (HPV) vaccines – NCI. Published online June 18, 2021. Accessed September 4, 2022.

4. Padala SA, Kallam A. Diffuse large B cell lymphoma. In: StatPearls. StatPearls Publishing; 2022.

5. Susanibar-Adaniya S, Barta SK. 2021 update on diffuse large B cell lymphoma: a review of current data and potential applications on risk stratification and management. Am J Hematol. 2021;96(5):617-629. doi:10.1002/ajh.26151

6. Xu-Monette ZY, Young KH. Therapeutic vaccines for aggressive B-cell lymphoma. Leuk Lymphoma. 2020;61(13):3038-3051. doi:10.1080/10428194.2020.1805113

7. Alaniz L, Rizzo MM, Mazzolini G. Pulsing dendritic cells with whole tumor cell lysates. Methods Mol Biol. 2014;1139:27-31. doi:10.1007/978-1-4939-0345-0_3

8. Granulocyte macrophage colony stimulating factor – an overview. ScienceDirect. Accessed September 9, 2022.

9. Frank MJ, Khodadoust MS, Czerwinski DK, et al. Autologous tumor cell vaccine induces antitumor T cell immune responses in patients with mantle cell lymphoma: a phase I/II trial. J Exp Med. 2020;217(9):e20191712. doi:10.1084/jem.20191712

10. Vaccination with Flt3L, radiation, and Poly-ICLC. ClinicalTrials.gov. Published online December 28, 2018. Accessed September 10, 2022.

11. Pembrolizumab. National Cancer Institute. Published online September 18, 2014. Accessed September 10, 2022.

12. A phase I study of intratumoral injections of CpG-STAT3 SiRNA (CAS3/SS3) in combination with local radiation in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). ClinicalTrials.gov. Published online August 9, 2021. Accessed September 25, 2022.

13. Méndez C, Ahlenstiel CL, Kelleher AD. Post-transcriptional gene silencing, transcriptional gene silencing and human immunodeficiency virus. World J Virol. 2015;4(3):219-244. doi:10.5501/wjv.v4.i3.219

14. Phase I/II study of dendritic cell therapy delivered intratumorally after cryoablation and anti-PD-1 antibody (pembrolizumab) for patients with non-Hodgkin lymphoma. ClinicalTrials.gov. Published online January 30, 2017. Accessed September 9, 2022.

15. Kuchar E, Karlikowska-Skwarnik M, Han S, Nitsch-Osuch A. Pertussis: history of the disease and current prevention failure. Adv Exp Med Biol. 2016;934:77-82. doi:10.1007/5584_2016_21

16. Phase I trial to assess safety and immunogenicity of xenogeneic CD20 DNA vaccination with patients with B-cell lymphoma. ClinicalTrials.gov. Published online November 21, 2007. Accessed September 25, 2022.

17. Phase 2 study of an immunotherapeutic vaccine, DPX-Survivac with low dose cyclophosphamide in patients with recurrent survivin-expressing diffuse large B-cell lymphoma (DLBCL). ClinicalTrials.gov. Published online December 23, 2014. Accessed September 25, 2022.

18. Phase 2 study of an immune therapy, DPX-Survivac with low dose cyclophosphamide administered with pembrolizumab in patients with persistent or recurrent/refractory diffuse large B-cell lymphoma (DLBCL). ClinicalTrials.gov. Published online November 21, 2017. Accessed September 25, 2022.

19. Berinstein NL, Bence-Bruckler I, Laneuville P, et al. Combination of DPX-Survivac, low dose cyclophosphamide, and pembrolizumab in recurrent/refractory DLBCL: the Spirel study. Blood. 2019;134:3236. doi:10.1182/blood-2019-125963